Received: 28 December 2019 Revised: 2 March 2020 Accepted: 2 April 2020

DOI: 10.1002/ptr.6703

REVIEW

Curcumin effect on cancer cells' multidrug resistance: An

update

Saeedeh Keyvani-Ghamsari1 | Khatereh Khorsandi2 | Asma Gul3

1
Department of Microbiology, Karaj Branch,
Islamic Azad University, Karaj, Iran
2
Department of Photodynamic, Medical Laser
Research Center, Yara Institute, ACECR,
Tehran, Iran
3
Department of Biological Sciences,
International Islamic University, Islamabad,
Pakistan
Correspondence
Khatereh Khorsandi, Department of
Photodynamic, Medical Laser Research Center,
Yara Institute, ACECR, Tehran, Iran.
Email: khorsandi.kh@ut.ac.ir
Chemotherapy is one of the main methods for cancer treatment. However, despite
many advances in the design of anticancer drugs, their efficiency is limited due to
their high toxicity and resistance of cells to chemotherapeutic drugs. In order to
improve the cancer therapy, it is essential to use the compounds that can overcome
drug resistance and increase treatment efficiency. Researchers have studied the
effects of natural compounds for the controlling various drug resistance mechanisms.
Curcumin is a natural phenolic compound which shows potent anticancer activities in
different tumors, alone or as an adjuvant with other antitumor drugs to prevent or
inhibit the survival and cancer progression by various mechanisms. The role of cur-
cumin in overcoming drug resistance was followed by reviewing different applica-
tions of curcumin in cancer therapy. Afterward, the clinical impacts of curcumin, role
of curcumin in decreasing drug resistance in different cancer cells and its mechanisms
were discussed. It has been demonstrated that curcumin regulates signaling path-
ways in cancer cells, reduces the expression of proteins related to drug resistance,
and increases the performance of antitumor drugs at various levels. Curcumin
reverses multidrug resistance mechanisms and increases sensitivity of resistance cells
to chemotherapy. This review mainly focuses on different mechanisms of drug resis-
tance and curcumin as a nontoxic natural substance to eliminate the effects of drug
resistance through modulation and controlling cell resistance pathways and eventu-
ally suggests curcumin as a potent chemosensitizer in cancers.

KEYWORDS

anticancer drug, cancer, chemosensitizer, curcumin, multidrug resistance

1 | I N T RO DU CT I O N Reddy, & Velmurugan, 2017). At the beginning of treatment,

There are different cancer treatment techniques such as surgery, che-
motherapy, radiation therapy, immunotherapy, hormone therapy,
targeted therapy, stem cell transplant, and precision medicine, that
alone or in combination are used for cancer patients (Palumbo
et al., 2013). Treatment for each person depends on the type of can-
cer and stage of its development. One of the types of cancer treat-
ment is chemotherapy which is defined as application of various drug
classes that could-kill cancer cells through different mechanisms
(Malhotra & Perry, 2003). It can also affect the normal cells (Aslam
et al., 2014; Chan & Ismail, 2014; Huang, Ju, Chang, Muralidhar
patients respond to chemical agent but unfortunately, cancer cells
become resistant to antitumor drugs over time leading to reduction
of life quality and longevity of the patient. In fact, drug resistance is
the main reason for the failure of chemotherapy (Pan, Li, He, Qiu, &
Zhou, 2016). Involved factors in the drug resistance are divided into
two major categories: genetic and epigenetic factors in cancer cells
that reduce the sensitivity of cells to drugs and factors that block
the access of cancer cells to the drugs (Nikolaou, Pavlopoulou, Geo-
rgakilas, & Kyrodimos, 2018). These factors arise due to several
mechanisms such as changes in the drug intake, increases efflux
due to overexpression of P-glycoproteins (P-gps), DNA damage

Phytotherapy Research. 2020;1–23. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons, Ltd. 1
2 KEYVANI-GHAMSARI ET AL.
repair, modified drug metabolism, and inhibition of cell death
(Vosooghi et al., 2014). The genetic and epigenetic diversity ulti-
mately favors the varieties of the resistance pathways available,
depending on the cancer itself; and even from an individual to indi-
vidual (Hervouet, Cartron, Jouvenot, & Delage-mourroux, 2013).
Therefore, the ability to predict and overcome drug resistance leads
to development of chemotherapy and increases the survival rate of
patients. Since the different drug groups target various pathways,
the chances of resistance to them decreases by using combination
therapy (Bozic et al., 2013). For this purpose, during the past
decades, many natural products which have chemosensitivity prop-
erties and derived from plants, animals, fungi, and microorganisms,
have been identified for combination therapy (Hamed, Abdel-Azim,
Shams, & Hammouda, 2019; Khazaei Koohpar, Entezari,
Movafagh, & Hashemi, 2015). Among phytochemicals, curcumin—
due to its low toxicity, side effects, and influence on various
cancers—has invited the attention of scientists. Curcumin is a poly-
phenol compound extracted from the Curcuma longa plant and is
commonly used as a spice (Goel & Aggarwal, 2010; Khazaei
Koohpar et al., 2015; Liu, Chen, Cui, & Zhou, 2005). It acts as an
antioxidant with anti-inflammatory, wound-healing, antiseptic, and
anticancer effects (Vallianou, Evangelopoulos, Schizas, & intestinal epithelium, liver cells, colon, proximal tubule of the kidney,
Kazazis, 2015; Wilken, Veena, Wang, & Srivatsan, 2011). Curcumin
has shown increased sensitivity of cancer cells to treatment by
targeting various stages of cancer including cell cycle regulation,
induction of apoptosis, reduction of metastasis, and reversal of
innate or acquired cellular resistance (Nabekura, 2010; Panda,
Chakraborty, Sarkar, Khan, & Sa, 2017). In the present review we
comprehensively describe different mechanisms of cellular resis-
tance (Zhang & Wang, 2017), and activity of curcumin as a chemo-
preventive agent that could overcome different drug resistance
pathways in cancer cells.
2 | T H E M E C H A N I S M S O F DR U G
RESISTANCE
2.1 | Increasing of drug efflux
One of the mechanisms which cause drug resistance is the excessive
efflux of the drug, which is carried out by ATP-binding cassette trans-
porters (ABC transporters; Housman et al., 2014). This superfamily
exists in all creatures from prokaryotes to humans. The structure of
these transporters has several subunits; two highly conserved cyto-
plasmic domains that bind to ATP with energy utilizing properties,
result in the release of various substrates across the cell membrane,
and two less conserved transmembrane domains (Wilkens, 2015). In
fact, by pumping toxins and drugs out of the cell, prevent the accumu-
lation of these substances in the cell and in normal conditions main-
tain cells from xenobiotics (Chang, 2003; Sarkadi, Homolya,
Szakács, & Váradi, 2006). In humans, 48 members of the ABC genes
have been seen that three members of them play a main role in
multidrug resistance (MDR), (a) P-gp, (b) MDR-associated protein
1 (MRP1), and (c) breast cancer resistance protein (BCRP/ABCG2;
Figure 1). P-gp which found in both normal and cancerous cells, in the
and blood–brain barrier could hydrolyzes two ATP to pump each drug
molecule or toxin from inside to outside the cell (Sarkadi et al., 2006).
And since it is present on the cells before chemotherapy is considered
as intrinsic resistance (Klopfleisch, Kohn, & Gruber, 2016). P-gp trans-
fers broad substrate including topoisomerase inhibitors, microtubule-
targeted drugs, tyrosine kinase inhibitors (TKIs), glucocorticoids, and
xenobiotics. Tissues such as lung, breast, and prostate that do not pro-
duce MDR, become resistant to drugs through the expression of
MDR1 and BCRP (Ambudkar, Kimchi-Sarfaty, Sauna, &
Gottesman, 2003; Housman et al., 2014). The structure and function
F I G U R E 1 Structure and function of
the multidrug ABC transporters. In
humans, the three major types of
multidrug resistance (MDR) proteins
include members of the ABCB (ABCB1/
MDR1/P-glycoprotein), the ABCC
(ABCC1/MRP1, ABCC2/MRP2, probably
also ABCC3–6, and ABCC10–11), and the
ABCG (ABCG2/MXR/BCRP) subfamily.
Multidrug/xenobiotic ABC transporters
are in the plasma membrane and extrude
various hydrophobic and/or amphipathic
xenobiotics and metabolic products.
MDR1/Pgp transports hydrophobic
compounds (X), while MRP1 and ABCG2
can extrude both hydrophobic drugs and
intracellular formed metabolites, for
example, glutathione or glucuronide
conjugates (C-X). Reprinted with
permission from Sarkadi et al. (2006).
ABC, ATP-binding cassette [Colour figure
can be viewed at wileyonlinelibrary.com]
KEYVANI-GHAMSARI ET AL. 3

of MDR1 is similar to P-gp, but it is GSH-dependent and only trans-
fers drugs that are modified by glutathione (GSH). Therefore, it influ-
ences when the drugs are metabolically activated. MDR1 plays a key
role in the development of resistance to drugs such as etoposide, vin-
cristine, doxorubicin, epirubicin, vinblastine, and vincristine
(Liu, 2009). The BCRP structure is a homodimer composed of two half
transporter which are linked by disulfide bond. Mitoxantrone, doxoru-
bicin, topotecan, irinotecan, flavopiridol, and epirubicin can be men-
tion as BCRP specific substrates (Liu, 2009; Robey, Polgar, Deeken,
To, & Bates, 2007; Sarkadi et al., 2006). Generally, overexpression of
these transporters in tumor cells has been observed to reduce the
accumulation of cytotoxic drugs in the cells which leads to cancer cell
survival and the development of MDR (Ambudkar et al., 2003).
2.2 | Increase in DNA damage repair
Chemotherapeutic drugs, whether directly or indirectly, target the
DNA. The change in DNA structure reduces replication and transcrip-
tion of the genes and eventually induces apoptosis in cells through
various pathways. One of the drug resistance mechanisms in cancer is
the removal of DNA damage that eliminates drug response and causes
tumor cells to survive (Stover, Konstantinopoulos, Matulonis, &
Swisher, 2016). In these cells, the DNA damage is identified by DNA
damage recognition proteins which activate a variety of DNA repair
systems depending on the type of lesion. DNA repair systems can be
categorized as base excision repair (BER), nucleotide excision repair
(NER), and mismatch repair (MMR) in single-strand damages and non-
homologous end joining (NHEJ), microhomology-mediated end joining
(MMEJ), and homologous recombination (HR) in double-strand breaks
(Salehan & Morse, 2013). For example, cisplatin induces crosslinks in
DNA structure that can cause cell death on the contrary, the resistant
cells escape from the damage with different repair mechanisms such
as NER and HR (Rocha, Silva, Quinet, Cabral-Neto, & Menck, 2018;
Figure 2). Studies on chronic myeloid leukemia cells have shown rate
of O6-ethylguanine elimination and repair in patients that are resis-
tant to alkylated drugs is higher than drug-sensitive patients (Müller,
Thomale, Rajewsky, & Seeber, 1998). Moreover, in genotoxic stress, if
DNA cannot be repaired, DNA damage can be tolerated by specialized
DNA polymerases in the resistance cells. These DNA polymerases
have flexible and larger active site that cause the replication pass
through the lesions by the translesion synthesis (TLS) pathway and
ultimately leads to mutation and drug resistance(Lehmann, 2005; Shi-
mizu et al., 2003). Studies have suggested that several specific poly-
merase enzymes are used in this system, one or two enzymes for
nucleotides addition and the other enzymes for expansion (Salehan &
Morse, 2013). Overexpression of these polymers and DNA damage
recognition proteins has been observed in various cancer cells
(Salehan & Morse, 2013; Srivastava et al., 2015) Studies reveal that
the overexpression of polymerase η reduces the susceptibility of

F I G U R E 2 Cisplatin-induced DNA
lesions and repair mechanisms that is
included: (a) The nucleotide excision
repair (NER) pathway for removing
cisplatin-induced DNA adducts (such as
1,2 and 1,3 intrastrand adducts), while the
mismatch repair (MMR) pathway can
recognize but not repair these adducts.
(b) Double-strand breaks are repaired by
homologous recombination (HR) and
nonhomologous end joining (NHEJ). The
NER, HR, translesion synthesis (TLS), and
Fanconi anemia (FA) pathways are
involved in ICL repair. (c) Schematic
representation of lesion bypass of
cisplatin-induced intrastrand crosslinks via
the TLS pathway. Reprinted with
permission from Rocha et al. (2018)
[Colour figure can be viewed at
wileyonlinelibrary.com]
4 KEYVANI-GHAMSARI ET AL.
ovarian cancer stem cells (CSCs) to cisplatin so that downregulation of
Pol η increased apoptosis in cells treated with cisplatin (Srivastava
et al., 2015). Another study has shown that expression of polymerase
η increases in gemcitabine and cisplatin-resistant head and neck squa-
mous cancer cell (Zhou et al., 2013).
2.3 | Altering the drug targets
During drug targeting, a drug often encounters resistance mecha-
nisms, such as modification of the special target of the drug through
mutation or alteration in the level of expression of its target which
results in a change in the quantity or quality of the drug target
(Alfarouk et al., 2015). For example, taxanes cause cancer cell death
through binding to tubulins. Reviews have shown the change in the
structure of tubulins due to gene mutation or inactivation of tubulin-
specific chaperons is a major cause of tubulin resistance in breast can-
cer. In addition, downregulation of tumor β III- and β V-tubulins has
been observed in the resistant cells (Nami & Wang, 2018). Irinotecan
binds to DNA topoisomerase I complex and through creating perma-
nent cleavages in DNA structure, inhibit reproduction and transcrip-
tion. The topoisomerase I expression reduced in colon cancer
resistance cells which reduced the sensitivity of the cells to the drug
(Boyer et al., 2004; Pommier, 2013). Tamoxifen is a selective estrogen
receptor (ER) modulator which is used for the treatment of breast can-
cer. Mutation in ER gene, its downregulate, and posttranslational
modifications of ER in breast cancer cells which prevent the binding
of tamoxifen to ER could be consider as one of resistance mechanisms
to tamoxifen (Criscitiello, Fumagalli, Saini, & Loi, 2011; Likhite, Stossi,
Kim, Katzenellenbogen, & Katzenellenbogen, 2006).
Tyrosine kinase inhibitors target the epidermal growth factor
receptor (EGFR) in the cells which generally their use fails after about
1 year. One of the main reasons for their resistance is mutations in
the kinase domain of EGFR genes. So, by mutations in the gatekeeper
residues the binding of drug to catalytic ATP-binding site in the kinase
domain of EGFR is prevented (Bell et al., 2005).
2.4 | Resistance to apoptosis
Apoptosis is programmed cell death through intrinsic and extrinsic
pathways under cellular stress or receiving death signals from other
cells. In the external pathway, binding of ligands to death receptors at
the cell surface activates caspases 8 and 10 that cleave and activate
effector caspases 7, 6, and 3 (Fulda & Debatin, 2006). Internal path-
way performed in the mitochondria, with creating apoptosome by
cytochrome c, Apaf-1, and procaspase 9 that activates caspase 9, 7,
6, and 3 (Pfeffer & Singh, 2018). In this process, the balance between
antiapoptotic proteins, such as Bcl2, Bcl-Xl, and AKT and the
preapoptotic proteins such as Bax, Bak, and Bid leads to apoptosis
(Baig et al., 2016; Figure 3). The raising of antiapoptotic factor expres-
sion and reduction the proapoptotic factor expression play a key role
F I G U R E 3 Schematic representation
of the extrinsic and intrinsic apoptotic
pathway which could be induced by
chemotherapy and radiotherapy drugs.
The increasing of antiapoptotic factor
expression (IAPs) and reduction the
proapoptotic factor expression (Bax, Bak,
and Bid) play a key role in progress of the
drug resistance. Reproduced with
permission from de Vries (2006). IAP,
Inhibitors of apoptosis [Colour figure can
be viewed at wileyonlinelibrary.com]
KEYVANI-GHAMSARI ET AL.
in progress of the drug resistance (Razaghi, Heimann, Schaeffer, &
Gibson, 2018; Siddik, 2003). Therefore, targeting these proteins is an
important factor in cancer treatment. The use of inhibitors of anti-
apoptotic proteins such as antisense oligonucleotides, antibodies, or
small molecule inhibitors induce apoptosis in the tumor cells and
enhance the effect of chemotherapy drugs, but studies have shown
their long-term use also causes resistance (Garc, Elisabet, &
Redondo, 2018; Soria et al., 2010). Inhibitors of apoptosis (IAPs) as
caspase inhibitors, also have remarkable role in the drug resistance
(Razaghi et al., 2018). Overexpression of X-linked IAP (XIAP) has been
seen in cancer cells whose its inhibition by short-interfering RNA
(siRNA) enhanced apoptosis in the cells and increased the effect of
chemotherapy on the cells (Wong, 2011). In addition, P53 is a tumor
suppressor protein cods by TP53 gene which effects the transcription
of the responsible genes in apoptosis and leads to apoptosis at the
time of DNA damage. Mutation and losing in Tp53 gene results in cell
proliferation despite gene damage in cancer cells. The mutation of this
gene occurs in various cancers in the range of 10–100%, this action
leads cancer cells ultimately resistance to the chemotherapy (Geisler
et al., 2003; Rivlin, Brosh, Oren, & Rotter, 2011; Talib, Al-hadid, Wild
Ali, Al-Yasari, & Abd Ali, 2018).
2.5 | Decreasing the activity of the drugs
Antitumor drugs could react with the proteins and enzymes in the
cells and be activate after structural changes. Changes to drug activa-
tion include modification, degradation, or the binding of drugs to
other molecules. But generally after beginning treatment, the drug
activation process in cancer cells is impaired and the toxic effect of
the drug is reduced (Zahreddine & Borden, 2013). Cytochrome P-450
(CYPs) and glutathione S-transferase (GST)/glutathione S-hydrolases
(GSH) and the uridine diphospho-glucuronosyltransferase (UGT)
superfamily could be mention as important enzymes for activating
and inactivation of drugs (Michael & Doherty, 2005). The cytochrome
P-450 superfamily enzymes are present in the inner membrane of
mitochondria or in the endoplasmic reticulum in the most tissues of
the body and have a wide range of substrates such as xenobiotic, ste-
roids, cholesterol, and hormones (P. B. Danielson, 2002). They are
Phase 1 enzymes in the metabolism of the most drugs such as cyclo-
phosphamide, epipodophyllotoxins, ifosfamide, teniposide, tamoxifen,
taxol, and vinca alkaloids. The mutation in cytochrome p450 genes, its
deficiency, and inhibition is responsible for the inactivation of these
drugs (Bibi, 2008; Talalay, 2000). The GST–GSH system is known as
Phase II metabolic isozymes that play an important role in the mecha-
nism of detoxification of drugs by catalyzing the conjugation of GSH.
They are potent antioxidant that protects cells against toxic com-
pounds, free radicals, and peroxidases. Although they have a positive
effect on the protection of the normal cells against reactive oxygen
species (ROS) which cause resistance in chemotherapy (Allocati, Mas-
ulli, Di Ilio, & Federici, 2018). The chemotherapeutic agents induce
and increase the expression of these proteins (Talalay, 2000; Wang,
Yang, Yang, Wang, & Lee, 2015). Increasing the activity of GST–GSH
5
system promote inactivation reactions of drugs and protects cells
against the chemotherapy. Additionally, the drug binding to GSH
increases the solubility of the drug and enhances the possibility of
drug exit from the cell by MDR proteins (Wang, Yang, et al., 2015).
The UGT (also called glucuronosyltransferase) family is a part of Phase
II metabolism that is responsible for glucuronidation to various sub-
strates such as bilirubin, bile acids, steroids, and drugs. UGT1 and
UGT2 are found in human that have important role in the body's met-
abolic defense system. It is reported epigenetic changes reduce the
expression of these genes in some cancers. In fact, DNA promoter
methylation of these genes leads to gene silencing that drugs such as
irinotecan are active in these conditions. However, studies have
shown overexpression of these genes causes resistance to irinotecan
and other drugs (Holohan, Van Schaeybroeck, Longley, &
Johnston, 2013; Pathania, Bhatia, Baldi, Singh, & Rawal, 2018).
2.6 | Role of epigenetic changes in MDR
Epigenetic modifications are another mechanism of drug resistance in
cancer treatment (Fardi, Solali, & Farshdousti Hagh, 2018). DNA
methylation and histone modification (acetylation or methylation) are
two main types of the epigenetic alterations directly affecting the pro-
moter of genes or indirectly alter chromatin conformation (Kanwal &
Gupta, 2012; Figure 4). These modifications alter the cell phenotype
by affecting gene expression without altering the genotype
(Miremadi, Oestergaard, Pharoah, & Caldas, 2007). More recently,
research has shown that these changes can lead to acquired drug
resistance. For example, hypomethylation in promoter regions of
oncogenes, upregulates the gene expression, and hypermethylation
reduces expression of tumor suppressor genes in cancer cells
(Baker & El-Osta, 2003). Modification of histones also results in relax-
ation or condensation of chromatin, thereby affecting gene expres-
sion. For example, H3K9 methylation at the promoter of many tumor
suppressors causes gene silencing. Whereas, histone acetylation gen-
erally cause chromatin to open and transcription factors can access
DNA-encoded regions (Hu & Baeg, 2017). Studies have shown inap-
propriate methylation of the ER promoter, histone deacetylation, and
hypoxia decreases receptor expression and leading to cell resistance
to tamoxifen (García-Becerra, Santos, Díaz, & Camacho, 2013). Other
studies have reported methylation at the MDR1 gene promoter regu-
lates the expression of this protein. Demethylation of MDR1 pro-
motor upregulates expression of the protein in the resistance cells
which reduces the accumulation of drugs inside the cell, whereas the
promoter of this gene is hypermethylated in drug-sensitive cells
(Baker & El-Osta, 2003; Klopfleisch et al., 2016). The Epigenetic
changes also affect the expression of DNA repair enzymes.
Hypermethylation in the promoter of MMR enzymes including the
human MutL homolog 1(hMLH1) and human MutS protein homolog
1 (hMSH1) result in gene silencing which can cause the development
of cancers (Klopfleisch et al., 2016). Epigenetic changes are reversible
by DNA methyl transferase (DNMT) inhibitors and histone
deacetylase (HDAC) inhibitors. For example, the epigenetic
6 KEYVANI-GHAMSARI ET AL.

F I G U R E 4 Three different epigenetic levels: DNA methylation, histone methylation or acetylation, and chromatin reading. The use of
demethylating agents and HDAC inhibitors offers the potential to change the gene expression profile of tumors lead to tumor cell death and
increased apoptotic response to chemotherapy drugs. Reproduced with permission from Jubierre et al. (2018). HDAC, histone deacetylase
[Colour figure can be viewed at wileyonlinelibrary.com]

modifications in hMLH1 and inactivation of this gene can lead to can-
cer progression and resistance to drugs such as cisplatin, carboplatin,
temozolomide, epirubicin, and 5-fluorouracil. However, the use of
DNMT inhibitors such as decitabine and azacytidine return the sensi-
tivity of cancer cells to drugs by reducing methylation of the hMLH1
promoter (Klopfleisch et al., 2016; Mansoori, Mohammadi, Davudian,
Shirjang, & Baradaran, 2017).
2.7 | MicroRNA and drug resistance
MicroRNAs (miRNAs) are small molecules of about 21–25 nucleotides
that are unable to encode a protein instead play a key role in posttran-
scriptional regulating of gene expression (Ghasabi et al., 2019). This
large family affects the expression of about 60% of genes encoding
proteins. MiRNAs are coupled to their complementary base
sequences in the 30 region of mRNAs, and through several mecha-
nisms silence mRNAs (Fabian, Sonenberg, & Filipowicz, 2010; Ghasabi
et al., 2019). These mechanisms include fragmentation of the mRNA
into two separates pieces, shorten the poly (A) tail in the mRNA struc-
ture that making it unstable, and block protein translation through the
ribosome. Therefore, they epigenetically control the expression of
genes such as tumor suppressors genes or oncogenes (Jalkanen, Col-
eman, & Wilusz, 2014). Recent studies have proven that miRNA dys-
regulation promotes the drug resistance in various cancers (Kumar,
Kushwaha, & Gupta, 2019). For example, downregulation of miR-127
and miR-34a reduced apoptosis in the MFC-7 cells treated with doxo-
rubicin by decreasing p53 signaling pathway. On the other hand,
upregulation of the miR- 206, miR-106a, miR-21, and miR-214 in
these cells reduced the expression of ERa, RB1, and PTEN proteins
and resulting in resistance to doxorubicin. Study on the expression of
MDR1 protein in MCF-7 cells has shown that the expression of this
protein is inversely related to expression of miR-451. Transfection of
these cells with miR-451 decreased MDR1 expression and therefore
increased cell susceptibility to doxorubicin (Kovalchuk et al., 2008).
Another study has shown miR-7 (as a tumor suppressor agent in vari-
ous cancers) downregulates in cetuximab-resistant cells. On the other
hand, increasing miR-133b in the tumor cells with the effect on EGFR
suppressed the growth of cells and increased the sensitivity of malig-
nant cells to cetuximab (Ghasabi et al., 2019). Upregulation of miR-
27a, miR-451, miR-99a, miR-100, and miR-125b1 was seen in the
drug-resistance ovarian and cervical cancer cells. The use of miR-27a
or miR-451 antagonists reduced P-gp and MDR1 at the cell surface
and consequently increased the concentration of the drugs inside the
cells (Ma, Dong, & Ji, 2010). Studies on tamoxifen-resistant breast
cancer cells have shown that about eight miRNAs upregulate and
seven miRNAs downregulate in the cells compared with tamoxifen-
sensitive cells (Miller et al., 2008). Since microRNAs can affect the
advancement of various stages of resistance, pay attention to them
can help to overcome the drug resistance (Figure 5).
2.8 | Role of CSCs in drug resistance
Cancer stem cells have been seen in hematopoietic and solid tumors.
They are capable of self-renewal and differentiation and play an
KEYVANI-GHAMSARI ET AL.
F I G U R E 5 Different Mechanisms of
multidrug resistance in cancer cell could
be classified into many different
mechanisms such as enhanced drug
efflux, enhanced DNA damage repair,
altering drug targets, inhibiting apoptosis,
decreasing the drug activity, cell cycle
checkpoints alternation, and epigenetics
alternation. MiRNAs could mediate drug
responses of cancer cells by targeting the
pathways related to resistance. Reprinted
with permission from Zhang and
Wang (2017) [Colour figure can be
viewed at wileyonlinelibrary.com]
important role in tumor initiation, invasion, metastasis, and drug resis-
tance (Najafi, Mortezaee, & Ahadi, 2019; Saha, Adhikary,
Bhattacharyya, Das, & Sa, 2012). CSCs are a small population of cells
within a tumor that mainly located in a special environment called the
niche with hypoxia, low pH, and low nutrition (Mondal,
Bhattacharya, & Mandal, 2018). They are surrounded by a variety of
cells such as fibroblasts, endothelial, mesenchymal, and immune cells
in the niche that promote self-renewal of CSCs (Prieto-Vila, Taka-
hashi, Usuba, Kohama, & Ochiya, 2017). According to one theory,
CSCs may be caused by genetic or epigenetic alterations of normal
stem cells. Another theory suggested that the origin of CSCs is muta-
tion in differentiated cancer cells (Mondal et al., 2018). Many studies
have shown that CSCs use both intrinsic and extrinsic resistance
mechanisms to escape death against antitumor drugs and exhibit
more resistance to chemotherapy than non-CSCs. Due to their unlim-
ited self-renewal ability, they can regenerate tumor cells after chemo-
therapy (Najafi, Mortezaee, & Majidpoor, 2019). Among the
mechanisms of resistance in CSCs, overexpression of ABC trans-
porters such as ABCB1, ABCG2, ABCB5, and ABCC1 on the surface
of these cells could be mentioned (Prieto-Vila et al., 2017). They also
avoid apoptosis by overexpression of antiapoptotic proteins such as
Bcl-2, surviving, and Mcl-1 or through disable cell cycle regulators.
The DNA damage–repair system is also highly active in these cells
(Najafi, Mortezaee, & Majidpoor, 2019; Tsai et al., 2012). Studies have
shown that epithelial–mesenchymal transition (EMT) regulators are
very effective in these cells. Due to the close association of EMT to
the biology of CSCs and the role of EMT on non-CSCs to transform
into CSCs, it is referred to another resistance factor in these cells
(Najafi, Mortezaee, & Ahadi, 2019; Wang, Sun, Provaznik, Hackert, &
Zöller, 2019). The next mechanism that causes resistance in CSCs is
the hypoxic position of the malignant stem cells which is the provider
of growth signals, transformation, and maintaining the stability of the
7
cell's self-renewal. Signaling pathways activated by hypoxia also
decrease ROS production in CSCs, and by creating a state of silence in
the cells develop resistance to treatment (Prieto-Vila et al., 2017;
Zhang et al., 2018). CSCs also have protective autophagic mechanisms
that maintain their stability (You et al., 2019). MiRNAs are another
factor that through epigenetic changes leads to the survival of CSCs,
their stemness and consequently drug resistance (Najafi, Mortezaee, &
Majidpoor, 2019). Therefore, given the importance of CSCs in tumor
maintaining and MDR in the treatment, targeting, and eliminating
them helps to overcome drug resistance.
3 | NA T U R A L P R O D U C T S OV E R C O M E
M D R I N C A N CE R C E L LS
Since different parts of the cell are targeted in cancer, treating the dis-
ease with one drug is almost impossible. In addition, the cells quickly
find ways to escape the mechanisms of drug functional and adapt to
therapy. The discovery of new drugs with high efficacy and low toxic-
ity that have selectively is one of the goals of cancer treatment. In
recent decades, the use of natural compounds has attracted the atten-
tion of scientists in cancer therapy (Nobili et al., 2009). These com-
pounds have been used for centuries to treat a variety of diseases and
are taken from various parts of the plant tissues. Currently, many
patients from Australia, Europe, and the United States are using herbal
compounds in their combination therapies (Ekor, 2014). Natural com-
pounds due to their high efficacy and low toxicity and chemo-
sensitizing activities are quite convenient in combination therapy
(Aung, Qu, Kortschak, & Adelson, 2017). So far only about 10% plant
species have been identified for the treatment of various diseases.
Among natural compounds flavonoids, alkaloids, steroids, monoter-
penes, limonoids, saponins, polyphenols, and coumarins as anticancer
8 KEYVANI-GHAMSARI ET AL.
compounds could be mentioned (Eid, El-Readi, Fatani, Mohamed Nour
Eldin, & Wink, 2015; Iqbal et al., 2017; Millimouno, Dong, Yang, Li, &
Li, 2014). Phytochemicals could active or inhibit different enzymes in
cell proliferation, apoptosis, oncogenes, DNA repair signaling path-
ways and many of them act as chemopreventive agents (Nabekura,
Yamaki, Ueno, & Kitagawa, 2008). Flavonoids such as quercetin,
morin, citrus, curcumin, and capsaicin inhibit the drug efflux by the
inhibition of ABC transporters, MDR1, MRP, and BCRP with directly
connecting to the ATP-binding sites and in this way overcome MDR
(Conseil et al., 2002). Citrus flavonoids not only affect ABC trans-
porters but also regulate the function of metabolic enzymes (GST and
P450) in activation of chemotherapy agents (Eid et al., 2015).
Epigallocatechin gallate in tea, curcumin in turmeric, and capsaicin in
chili pepper reduce P-gp at the surface of human carcinoma KB-C2
cells in a concentration-dependent behavior, cause drug accumulation
within the cells and increase the sensitivity of these cells to daunoru-
bicin and vinblastine (Kitagawa, Nabekura, & Kamiyama, 2004;
Nabekura, 2010). Berberine through removing the MDR in K562/A02
cells increases cell sensitivity to adriamycin and doxorubicin (Meng,
Ze-Fa, Hua, & Bao-An, 2018).
3.1 | Curcumin
Among phytochemicals, curcumin has been considered because of its
potent anticancer properties and minimal side effects. Curcumin is an
active polyphenolic pigment of turmeric derived from Curcuma longa
rhizomes, generally grows in tropical logic, especially in Southeast Asia
that its use dates back to about 5,000 years ago that was generally
used as an inflammation reducing agent in infection and autoimmune
diseases (Panda et al., 2017; Pongrakhananon & Rojanasakul, 2012). It
is known for its antioxidant, anti-inflammatory, wound-healing, and
anti-carcinogenesis properties that prevent the beginning or develop-
ment of the cancer (Khorsandi et al., 2015; Krausz et al., 2015). One
of the major problems of using curcumin is its poor solubility, low
absorption, and limited tissue distribution. Encapsulation of curcumin
in liposome, micelles, silica, intercalated into cyclodextrine
nanoparticles or into layered double hydroxide (LDH) nanohybrids are
one of the few solutions (Khorsandi et al., 2015; Khorsandi,
Hosseinzadeh, & Shahidi, 2019) that remove the drug restrictions and
enhance the effectiveness of the curcumin (Khorsandi et al., 2019;
Krausz et al., 2015; Rai, Pandit, Gaikwad, Yadav, & Gade, 2015). Cur-
cumin inhibits ABC transporters, regulates production of metabolic
enzymes Phase I and II, downregulates genes that respond to DNA
damage such as ATM, ATR, BRCA1, and O6-methyl guanine-DNA
methyl transferase (MGMT) in cancer cells (Mori et al., 2006; Saha
et al., 2012). Microarray studies have shown that, the expression of
104 genes changes in the apoptotic signaling pathways with the pres-
ence of curcumin. In addition to apoptosis, curcumin affects the regu-
lation of metastatic, angiogenesis, cell cycle checkpoints, and immune
system signaling pathways (Ramachandran et al., 2005; Saha
et al., 2012). In general, main anticancer activities of curcumin include
inhibition of tumor formation, induction of apoptosis death, and
suppressing tumor progression (Figure 6). This findings show curcumin
can increase susceptibility of cancer cells to chemotherapy. Also, cur-
cumin is used alone or in combination with other drugs to treat vari-
ous types of cancers such as breast, colon, head and neck cancer,
melanoma, pancreas, and lung (Panda et al., 2017).
4 | C U R C U M I N O V E R C O M ES D R U G
RESISTANCE
As previously described, the main problem in cancer treatment and
chemotherapy is the toxicity of drugs in the normal cells and the resis-
tance of cancer cells to the mechanism of action of drugs that thereby
evade apoptosis. Numerous studies have demonstrated the ability of
curcumin to resolve drug resistance. There are some purposed mecha-
nisms for curcumin ability to overcome drug resistant that could be
described as below.
4.1 | Inhibition of drug efflux
Lack of accumulation of drugs within the cancer cells due to over-
expression of ABC transporters plays an important role in MDR. Cur-
cumin inhibits ABC family transporters such as ABCA1, ABCB1,
ABCC1, and ABCG2 in various cancer cells. For example, in cervical
cancer cells curcumin reduces the expression of ABCB1 (P-gp) protein
at the surface of cells as well as by interacting with the P-gp binding
sites, significantly decreasing the activity of this transporter (Table 1).
Treatment of these cells with vinblastine plus curcumin leads to accu-
mulation of vinblastine within the cells and increases the sensitivity of
the cells to the drug (Limtrakul, Anuchapreeda, & Buddhasukh, 2004;
Zhang, Chen, Wang, Peng, & Cai, 2014). Research has shown cur-
cumin to reduce ABCG2 function, increases the sensitivity of tumor
cells expressing this transporter to drugs such as, SN-38, doxorubicin,
topotecan, and mitoxantrone (Chearwae, Shukla, Limtrakul, &
Ambudkar, 2006). Others have also shown combination of 5 mg doxo-
rubicin and 5 mg curcumin in nanoparticle formulation increases
doxorubicin retention in the nucleus and enhances doxorubicin toxic-
ity in K562 cells. Curcumin inhibits MDR1, Bcl-2, and BCR/ABL gene
expression in these cells and by eliminating cellular resistance
enhances doxorubicin efficacy in the cells (Misra & Sahoo, 2011).
Therefore, curcumin is a useful agent in combination with important
chemotherapy drugs to overcome MDR.
4.2 | Induction of DNA damage
Another factor in drug resistance was the inhibition of DNA damage
caused by antitumor drugs. There are many evidences in relation to
the inhibition of DNA repair special enzymes by curcumin and also
curcumin induces DNA damage in different cell lines (Lu et al., 2009;
Rowe, Ozbay, O'Regan, & Nahta, 2009; Figure 7). Real-time results in
mouse–rat hybrid retina ganglion cell line N18 showed that 20 μM of
KEYVANI-GHAMSARI ET AL. 9

F I G U R E 6 Main anticancer
activity of curcumin such as
inhibition of tumor formation,
induction of apoptosis death, and
suppressing tumor progression
[Colour figure can be viewed at
wileyonlinelibrary.com]

TABLE 1 Curcumin and its derivatives with P-gp modulatory effect

Compounds
Unsymmetrical curcumin mimics
with various amide moieties
Heterocyclic cyclohexanone
monocarbonyl analogs of
curcumin
Chloro and asymmetrical series of
synthetic curcumin derivatives
Diketone and cyclohexanone
curcumin analogs
Inhibitors of Inhibitors of
MDR cancer model P-gp function P-gp expression References
MDR cervical adenocarcinoma X (Um et al., 2008)
Human embryonic kidney cells and X (Revalde, Li, Hawkins,
canine kidney cells transfected Rosengren, &
with wild-type P-gp Paxton, 2015)
MDR acute lymphoblastic leukemia X (Ooko et al., 2016)
MDR chronic myeloid leukemia X X (Mapoung et al., 2016)

Abbreviation: MDR, multidrug resistance.

curcumin for 48 hr decreases the expression of DNA damage–response
genes such as; ATM, ATR, BRCA1, DNA-PK, and MGMT (Lu et al., 2009).
Other studies have shown that curcumin induces DNA damage, modu-
lates BRCA1, and maintained this protein within the cytoplasm in triple-
negative breast cancer cells, loss of BRCA1 in nucleus prevents the repair
of the DNA and induces apoptosis in these cells (Rowe et al., 2009). In
one study, it was shown that curcumin inhibits the FA/BRCA pathway in
cyclophosphamide resistant human lymphoma cell line HT/CTX. As
FA/BRCA pathway regulates the cellular response to DNA damage, cur-
cumin reverses the cyclophosphamide resistance in HT/CTX cells and
increases the drug toxicity in these cells (Ji, 2010). In CH12F3 lymphoma
cells, 5 μM of curcumin sensitized cells to various DNA damage drugs
including cisplatin, methyl methanesulfonate, hydroxyurea, and camp-
tothecin. In these cells curcumin-induced DNA break through regulating
Rad51-dependant HR. HR is a main pathway in repairing double-strand
breaks induced by antitumor drugs and Rad51 is an essential factor in
HR pathway. Curcumin downregulated the expression of Rad51 and
removed the resistance of the cells to the drugs which ultimately lead to
the induction of caspase3-dependent apoptosis (Zhao et al., 2018).
4.3 | Disable epigenetic changes
As mentioned earlier, epigenetic changes play an important role in the
development of drug resistance in cells. There are many reports in
relation to suppress DNMT by curcumin.
Studies on binding of curcumin to DNMT1 via molecular docking
have shown that curcumin binds covalently to the catalytic active site
of DNMT1 and blocks it (Liu et al., 2009). Another study has shown
10 μM of curcumin inhibits DNMT1 in acute myeloid leukemia (AML),
both in vitro and in vivo. In addition, it downregulates the positive
regulators of DNMT1, including p65 and Sp1 which reduces the
10
F I G U R E 7 Curcumin-induced DNA damage and inhibition of
DNA repair associated protein expression in human cervical cancer
HeLa cells. Reproduced with permission from Shang et al. (2016)
binding of these factors to the DNMT1 promoter. DNA hyp-
omethylation plays an important role in activating tumor suppressor
genes in AML, therefore proving curcumin a potent agent in the treat-
ment of AML (Boyanapalli & Kong, 2015). In hepatocellular carcinoma
that curcumin inhibits cell proliferation and induce apoptosis with
reduction in expression level of DNMT1 (Sanaei & Kavoosi, 2018).
Another study in vivo and in vitro showed, reduction of DNA
F I G U R E 8 Curcumin disable epigenetic changes. Curcumin could alter DNA methylation, histone modifications, and miRNA activity.
Reproduced with permission from Hassan et al. (2019) [Colour figure can be viewed at wileyonlinelibrary.com]
KEYVANI-GHAMSARI ET AL.
methylation through inhibition of DNMT3b by curcumin increased
expression of phosphatase and tensin homolog (PTEN), which plays
an effective role in inhibiting cell proliferation and inducing apoptosis
in hepatic stellate cells (Zheng et al., 2014). In addition to DNA meth-
ylation, acetylation of histones plays key role in gene expression
changes. Therefore, HDAC inhibitors are considered in the treatment
and enhancement of cell response to the chemotherapy (Reuter,
Gupta, Park, Goel, & Aggarwal, 2011). Bora-Tatar et al. have shown
that μM doses of curcumin has a potent inhibitory effect on HDAC, as
its effect is stronger than the known HDAC such as valproic acid and
sodium butyrate (Bora-Tatar et al., 2009). In B-NHL cell line Raji cells,
curcumin has reduced the expression of HDAC1, HDAC3, and
HDAC8 proteins thereby increasing the expression of acetylated his-
tone H4 and induces apoptosis (Liu et al., 2005). Another study has
shown that curcumin reduces expression of HADC4 in medulloblas-
toma cells which leads to increased tubulin acetylation. Ultimately,
inhibiting cell growth at the G2/M phase and inducing apoptosis in
the cells (Lee et al., 2011; Figure 8).
4.4 | Inhibition of metabolic enzymes
As explained above, overexpression of Phase II metabolic isozymes
plays an important role in the inactivation of drugs within the cell, so
the use of their inhibitors can be effective in preventing the
KEYVANI-GHAMSARI ET AL.
development of drug resistance. Studies have shown that curcumin
reduces glutathione transferases (GSTs) activity at both gene and pro-
tein levels. For example, in human IGR-39 melanoma cells, curcumin
inhibited GST activity through covalent modification of the enzyme
and in K562 cells strongly reduced the expression of GST P1-1 mRNA
(Mathew, Kalyanasundaram, & Balaraman, 2006). Downregulation of
GSTP1-1 mRNA by curcumin in K562 cells is associated with inhibi-
tion of TNF-α, AP-1, and NF-κB binding to the GST P1-1 gene pro-
moter (Duvoix et al., 2003). The effect of curcumin on Phase II
enzyme in rat liver is dose-dependent. Low concentrations of
curcumin-induced GST expression while high concentrations inhibited
GST expression (Mathew et al., 2006). On the other hand, a number
of studies reported curcumin induces GST expression in the cells,
which is effective in removing toxic and oxidizing substances and thus
playing an important role in the prevention of cancer in early stages
(Nishinaka et al., 2007; Syng-Ai, Kumari, & Khar, 2004). The effects of
curcumin on cytochrome P450 2C9 (CYP2C9) in human and cyto-
chrome P450 2C11 (CYP2C11) in rat liver microsomes revealed that
curcumin inhibits the activity of these cytochromes in a noncom-
petitively manner for the enzyme substrate and uncompetitive for the
cofactor NADPH. Given the role of CYP2C9 in activating a number of
the drugs, more attention should be paid when curcumin combined
with drugs that are metabolized by CYP2C9 (Wang et al., 2015). The
use of curcumin in rats has shown that curcumin decreases P-gp and
activates CYP 3A4 in vivo and ex-vivo, since CYP 3A4 is required to
metabolize more than 50% of drugs and also has a positive role in
activating multiple drug–drug interactions, curcumin can be a useful
agent for the activation of certain medicines (Hsieh et al., 2014).
4.5 | Curcumin effect on NF-κB expression
There are many reports about the inhibitory effect of curcumin on
inflammatory activities in various tumors through NF-κB inhibition
(Escárcega, Fuentes-Alexandro, García-Carrasco, Gatica, & as miR-1, miR-7, miR-9, miR34a, miR-21, miR-27, miR-181, and miR-
Zamora, 2007). NF-κB is a nuclear transcription factor that has a key
role in the cell proliferation, cell survival, and inflammatory responses.
It is required for the expression of cytokines, growth factors, onco-
genes, and cell cycle regulators (Spiros, 2017; Xia et al., 2018). NF-κB
regulates the expression of responsible genes for the immune system
and inflammation. The potential connection between chronic inflam-
mation and the initiation of cancer has been proven (Escárcega
et al., 2007; Jacob, Wu, Zhou, & Wang, 2007).
Improper regulation of NF-κB has been seen in many types of
cancer, moreover it increases in the presence of most anticancer
drugs in the cancer cells. NF-κB induces antiapoptotic proteins and
rises MDR protein expression that leads to cell viability and cellular
resistance in cancer cells (Xia et al., 2018). Curcumin inhibits constitu-
tive NF-κB activity and blocks NF-κB binding to the DNA whereby
reduces the expression of genes regulated by NF-κB such as TNF,
IkBa, Bcl-2, Bcl-xl, COX-2, and IL-6 genes in various cancer cells
(Shishodia, Amin, Lai, & Aggarwal, 2005). Downregulation of NF-κB in
the presence of curcumin has been observed in mantle cell lymphoma,
11
oral, MCF-7, and non-small cell lung carcinoma that limits the prolifer-
ation of cancer cells, causes cellular accumulation in the G1 phase and
also increases the sensitivity of the cells to the drugs (Meiyanto
et al., 2014; Shishodia et al., 2005). Overexpression and continuous
NF-κB activity has been observed in human head and neck squamous
cell carcinoma cell lines. It has been proven that curcumin suppresses
the activity of NF-κB in these cells through inhibition IκBα kinase
which is essential for the activation of NF-κB (Aggarwal, Takada,
Singh, Myers, & Aggarwal, 2004).
Curcumin also downregulates NF-κB expression by blocking the
PI3K/AKT pathway. NF-κB inhibition directly affects P53 activation,
on the other hand, inhibits the expression of COX-2 and VEGF genes
thereby reducing angiogenesis in cancer cells. Studies have shown
that the combination of 5-fluorouracil (5-FU) with curcumin signifi-
cantly reduces tumor growth in mice-bearing human gastric cancer
xenografts compared with the use of 5-FU alone. The results showed
this combination reduces the level of NF-κB and COX-2 protein by
37 and 45%, respectively. In fact, curcumin suggested the well-known
natural compound that inhibited NF-κB activity and increased the
sensitivity of cancer cells to treatment (Mortezaee et al., 2019). Cur-
cumin also inhibits cyclin D1 activity through NF-κB inhibition as seen
in head and neck squamous carcinoma (Aggarwal et al., 2004). Arrest-
ing the growth of cancer cells at various stages by curcumin can be
one option to overcome MDR.
4.6 | Regulation of miRNAs
MiRNAs dysregulates in many tumors and through the influence on
the different molecular and cellular pathways such as NF-κB, protein
kinase B, VEGF, MAPK, and cell cycle play an important role in the
proliferation, apoptosis, migration, and the resistance of cells to che-
motherapy (Boyanapalli & Kong, 2015; Mirzaei et al., 2018). Several
studies have shown that curcumin regulates miRNAs expression such
186 thereby inhibiting proliferation of cancer cells and also increases
the sensitivity of cells to antitumor drugs (Mirzaei et al., 2017).
Research on cloned cancer cells has shown that expression of miR-21
is increased in these cells which induces cell proliferation and metas-
tasis via reducing the expression of several proteins. One of the tar-
gets of miR-21 is the tumor suppressor PDCD4 that downregulated in
the presence of miR-21. The effect of 5–20 μM of curcumin for 24 hr
on clonal cancer cells has shown that curcumin significantly down-
regulates miR-21 in primary tumors and also inhibits cell growth in
invasive and metastatic cells (Mudduluru et al., 2011). Another miR-
21 target is tumor suppressor protein PTEN, which inhibits cell prolif-
eration by affecting the cell cycle. One study has shown that
difluorinated-curcumin (CDF) one of the curcumin derivatives
decreases the expression of miR-21 in chemoresistant cells of colon
cancer thereby increased the PTEN level and suppressed the drug-
resistant cells proliferation (Roy, Yu, Padhye, Sarkar, &
Majumdar, 2013). Studies on breast cancer cells have shown that cur-
cumin upregulates miR-15a and miR-16 in these cells, which both of
12
them inhibits the expression of Bcl-2. As a result, depletion of this anti-
apoptotic protein induced apoptosis in the cells (Yang, Cao, Sun, &
Zhang, 2010). Microarray analysis has shown that curcumin upregulates
expression of miR-22, miR-200c, let-7 g*, and miR-923 which are
tumor suppressor and downregulates expression of 16 miRNAs in reti-
noblastoma cells, ultimately reducing cell proliferation and migration
(Sreenivasan, Thirumalai, Danda, & Krishnakumar, 2012). Another arti-
cle reports that curcumin and its derivative CDF regulate the expres-
sion of miRNAs such as miR-21, miR-22, miR-200b, mir-200c in
pancreatic cancer cells. Upregulation of miR-22 decreased the expres-
sion of the Sp1 transcription factor and ER 1, thus inhibited the cell
proliferation. Overexpression of miR-200b and 200c also induced the
reversal of epithelial-to-mesenchymal transition in gemcitabine-
resistant pancreatic cancer cells (Simental-Mendía & Sahebkar, 2016).
Therefore, curcumin, due to its importance in regulating the expression
of miRNAs, can be considered as an important agent for cancer treat-
ment as well as overcoming drug resistance.
4.7 | The effect of curcumin on CSCs
Recently, numerous studies have shown that curcumin can inhibit
CSCs proliferation in various cancers. The inhibition can be due to
impacts on CSC self-renewal pathways such as Wnt/b-catenin, notch,
and sonic hedgehog. Several studies have demonstrated that cur-
cumin reduces catenin transcription in various cancer cells, leading to
decreased catenin levels, and inactivating the Wnt/b-catenin signaling
pathway (Li & Zhang, 2014). The notch signaling pathway is also der-
egulated in CSCs. Curcumin treatment decreased notch-1 activity in
esophageal squamous carcinoma cells through reducing γ-secretase
complex components expression. Curcumin also downregulated miR-
21 and miR-34 as notch-1 specific microRNAs and significantly
upregulated tumor suppressor let-7a miRNA. Therefore, curcumin
reduced cell proliferation and CSCs population in the surviving cells
after treatment (Subramaniam et al., 2012). Downregulation and inac-
tivation of notch-1 and NF-κB protein levels has also been reported in
pancreatic and oral cancer cells (Li & Zhang, 2014; Subramaniam
et al., 2012). Curcumin also can affect specific miRNAs in CSC to
remove the formation of the acquired EMT phenotype (Li, Kong,
Wang, & Sarkar, 2010). For example, researchers have reported that
miR-200 reduces the formation of CSCs by downregulation of
notch-1 and EMT regulators. But, it is reduced in chemotherapy resis-
tant cells which led to an increase in EMT phenotype. Studies have
shown curcumin and its analog CDF both increase the expression of
miR-200b and miR-200c in gemcitabine-resistant pancreatic cancer
cells and lead to the removal of EMT (Ali et al., 2010). The inhibitory
effects of curcumin on breast cancer stem cells (BCSCs) have also
been studied. Curcumin deregulated the process of EMT in breast
cancer cells by reducing the proteins that play a key role in the forma-
tion of EMT such as Slug, AXL, twist1, N-cadherin, β-catenin,
vimentin, and fibronectin (De, Beligala, Birkholz, & Geusz, 2019). The
studies demonstrated the combination of curcumin with mitomycin C
allows BCSCs to grow only the fourth generation. The size of the
KEYVANI-GHAMSARI ET AL.
BCSC population also reached about 25% of untreated cells. In addi-
tion, curcumin increased the sensitivity of cancer cells to mitomycin
C. This combination deregulated Bcl/Bax complex, increased
caspase-3 and caspase-9 activity thus increased apoptosis in BCSCs
(Liu & Ho, 2018).
4.8 | Curcumin analogues and their effect on the
removal of antitumor drug resistance
Despite the widespread function of curcumin in inhibiting the growth
of cancer cells, its clinical use is problematic. The main problems of
the use of curcumin are its poor solubility, low absorption, limited tis-
sue distribution, and rapid metabolism. One strategy to remove these
problems is to synthesize new curcumin analogues to increase its bio-
availability while maintaining its ideal effectiveness. Modification of
the curcumin structure enhanced its activity, penetration into the cell,
and increased the physiological and biological properties of curcumin.
So far, many high-efficacy curcumin analogs have been synthesized
(Mbese, Khwaza, & Aderibigbe, 2019; Murakami et al., 2017). One of
them is EF24, an excellent compound that has more bioactivity, anti-
tumor, and anti-inflammatory activity than curcumin. It inhibited cell
cycle and induced apoptosis in cancer cells by inhibiting NF-κB,
inhibiting HIF-1α, regulating ROS production, and regulating key
genes by miRNA. in vivo experiments have shown that EF24 sup-
presses the growth of breast cancer cells with low toxicity in a mouse
xenograft model (He, Li, Hu, Sun, & Kong, 2018). Another report
showed EF24 enhances the susceptibility of ovarian cancer resistant
cells to cisplatin via overexpression of p53 and p21 proteins in G2/M
checkpoint and consequently induces cellular arrest. It also induced
apoptosis in cisplatin-resistant cells by activating PTEN phosphoryla-
tion, inhibiting Akt and MDM2, and increasing p53 levels in the resis-
tance cells (Selvendiran et al., 2007). Another analog curcumin is GO-
Y035, which showed more inhibitory effect on clonal cell growth cell
line DLD-1 among the 2000 synthetic organic compound. Therefore,
according to the GO-Y035 structure, more than 50 curcumin ana-
logues were synthesized. Studies of GO-Y030, GO-Y078, GO-Y168,
and GO-Y172 analogs on ABCG2 transporter have shown that these
compounds can inhibit mitoxantrone and pheophorbide A efflux from
the ABCG2 in resistance K562/BCRP cells. In addition, cytotoxicity
assays showed that GO-Y030 and GO-Y078 increase the efficacy of
SN-38 in these cells. Therefore, these analogs can remove the
ABCG2-dependent MDR in the resistance cells (Murakami
et al., 2017). CDF is another analogue of curcumin. Its bioavailability is
high and various studies have shown a lower concentration is needed
compared to curcumin. The combination of CDF with gemcitabine
had a synergistic effect on pancreatic cancer cells. This combination
inhibited NF-κB activation and induced apoptosis in the cells. In addi-
tion, CDF reduced the expression of miR-21 that is overexpressed in
gemcitabine-resistant cells. Downregulation of miR-21 increased the
expression of PTEN and consequently induced cellular arrest
(Kwon, 2014). Another study showed that combination of CDF with
5-fluorouracil and oxaliplatin (5-FU + Ox) had more growth-inhibitory
KEYVANI-GHAMSARI ET AL.
F I G U R E 9 Chemical
structures of curcumin (a) and its
novel synthetic analogs (b).
Reprinted with permission from
Mimeault and Batra (2011)
[Colour figure can be viewed at
wileyonlinelibrary.com]
in resistant colon cancer cells than curcumin. It reduced the expres-
sion of ABCG2 in the resistant colon cancer cells and strongly
inhibited the growth of the CSCs. This combination inhibited activa-
tion of EGFR and IGF-1R signaling pathways, reduced activation of
β-catenin and NF-κB, downregulated the expression of c-Myc and
Cox-2, and increased proapoptotic protein Bax and caspase-3 activity.
Therefore, compared to curcumin, CDF induced a higher percentage
of apoptosis in chemoresistant colon cancer cells (Kanwar
et al., 2011). Tripathi and Misra have designed a number of new cur-
cumin analogues (compounds 1–6) that bind to P-gp at the surface of
BCSCs and inhibited drug efflux process, thereby removing drug resis-
tance in these cells and inhibiting cancer cell growth. Among the
designed analogues, glucoside of curcumin was more likely to bind to
P-gp in the BCSCs (Tripathi & Misra, 2016). Dimethoxy-curcumin
(DMC) is a lipophilic derivative of curcumin. It has been recognized as
a potent anticancer agent in colon cancer. DMC-induced apoptosis in
cloned cancer cells with less toxicity and side effects on normal cells
than curcumin (Mbese et al., 2019). Therefore, as mentioned, the cur-
cumin derivatives (Figure 9) overcome the disadvantages of curcumin
to enhance effectiveness of curcumin in cancer cell and remove drug
resistance.
4.9 | Curcumin delivery systems: Role of
nanotechnology
In addition to the synthesis of curcumin derivatives, another strategy
that can overcome the low bioavailability and poor pharmacokinetic
13
of curcumin is the use of delivery systems. A proper delivery system
should increase the activity and toxicity of curcumin over free cur-
cumin, while not having side effects on the normal cells. Among many
nano-based delivery groups, we will discuss some of them in this
section.
Liposomes are one of curcumin delivery systems. They consist of
two phospholipid layers and one aqueous nucleus therefore can carry
both hydrophobic and hydrophilic compounds. Liposomes increase
the stability of curcumin, its gastrointestinal absorption, and conse-
quently increase curcumin level in plasma (Yallapu, Jaggi, &
Chauhan, 2013). Various types of polymers have been used to design
nanoparticles for deliver curcumin. Synthetic polymers and natural
polymers used in drug delivery systems must be biocompatible and
biodegradable. Due to these properties, synthetic polymers such as
PLGA (poly(D, L-lactic-co-glycolic acid)) is commonly used in the cur-
cumin delivery system (Tomeh, Hadianamrei, & Zhao, 2019). A num-
ber of studies have shown that curcumin-loaded PLGA nanoparticles
(Cur-NPs) increase the oral bioavailability of curcumin. This formula-
tion increased water solubility, permeability, and inhibited P-gp
mediated-efflux of curcumin. Another study reported curcumin-
loaded PLGA nanoparticles conjugated to P-gp (CUR-NPs-APgp) indi-
cated a higher affinity for drug-resistant cervical carcinoma cell line
KB-V1compared to curcumin and Cur-NPs. Given that P-gp is over-
expressed in these cells and it is associated with aggressive behaviors
and MDR in KB-V1 cells, use of this formulation increased the uptake
of curcumin and enhanced its toxicity in these cells (Punfa, Yodkeeree,
Pitchakarn, Ampasavate, & Limtrakul, 2012). Another study reported
the effect of encapsulating curcumin and paclitaxel in flaxseed oil
14
containing nanoemulsion in ovarian cancer resistant cells. This formu-
lation effectively delivers the drugs to the cells. NF-κB activity and P-
gp expression decreased in the resistant cells and apoptosis signifi-
cantly increased in the presence of this combination (Ganta &
Amiji, 2009). Application of curcumin nanoparticle formulation has
been shown to strongly inhibit cell growth and induce apoptosis in
cervical cancer cells compared to free curcumin (Zaman et al., 2016).
Formulation of curcumin as curcumin/MPEG-PLA micelles increased
the toxicity of curcumin in a way that induced a higher percentage of
melanoma cells to apoptosis (Wang et al., 2017). Other researchers
have found curcumin-loaded lipo-PEG PEI complexes (LPPC) increases
curcumin accumulation in B16F10 cells and enhances the toxicity of
curcumin up to fivefold in curcumin-sensitive cells and up to 20-fold
in curcumin-resistant cells. Curcumin/LPPC inhibited cell cycle at
G2/M phase and increased the induction of apoptosis in the cells (Lin
et al., 2012). LDH has been used as drug delivery system due to their
good biocompatibility, low cytotoxicity, unique anionic exchange
property, and pH controlled release property in acidic environments
(especially cancer cells environment; Rives, Del Arco, & Martín, 2013).
Recently Khorsandi et al. intercalated curcumin into LDH nanohybrid
to remove the drug resistance and enhance the effectiveness of the
curcumin in photodynamic therapy against breast cancer cells
(Khorsandi et al., 2015, 2019). Silica-based nanoparticles also use as
deliver system for curcumin due to their resistant to changes in pH,
temperature, microbial, and enzymatic attack. (Couleaud et al., 2010).
Mirzahosseinipour et al. showed that the antimicrobial and antibiofilm
activities of curcumin-silica nanoparticle-aPDT against P. aeruginosa
and S. aureus was increased compare to alone curcumin
(Mirzahosseinipour, Khorsandi, Hosseinzadeh, Ghazaeian, & gp (ABCB1), MRP1 (ABCC1), BCRP (ABCG2) and increase the toxicity
Shahidi, 2020).
4.10 | Combination of curcumin with anticancer
drugs
Recently, significant consideration has been made on combination
chemotherapy in cancer using plant derived-bioactive substances. In
this part, we will explain recent studies in the combination of cur-
cumin with different anticancer drugs.
Meiyanto et al. has shown that combination of curcumin and its
derivatives with doxorubicin enhance the toxicity of doxorubicin in
resistant breast cancer cells through inhibition of HER2 and reduction
of NF-κB activation (Meiyanto et al., 2014). Royt et al. reported that
curcumin overcomes the drug resistance of cyclophosphamide and
paclitaxel in breast cancer cells via downregulation of telomerase, NF-
κB, and HDAC (Wei, Pu, & Zhao, 2017). Curcumin enhances the effect
of a HDAC inhibitor such as tricostatin A on cell cycle arrest in G0/G1
phase in breast cancer cell lines MDA-MB435eB and SkBr3. This com-
bination showed no change in p53 expression, increased p21, p27 and
reduced cyclin D1 protein expression. Also, curcumin increased pro-
tein expression of phosphorylated JNK and induced cleavage of
caspase 3 and PARP. These results suggested combination of cur-
cumin with tricostatin A induce p53 independent apoptosis via JNK
KEYVANI-GHAMSARI ET AL.
activation (Yan, Graham, & Lanza-Jacoby, 2013). High levels of flap
endonuclease 1 (FEN1) expression has been observed in cisplatin
resistance in breast cancer cells. FEN1 is an enzyme involved in DNA
replication and BER. Curcumin effectively reduced breast cancer cells
resistance to cisplatin through decreasing FEN1 expression (Zou
et al., 2018). Combination of curcumin with 5-Fluorouracil (5-FU) sig-
nificantly increased cell apoptosis in breast cancer cells compared to
5-FU alone and chemosensitized cells to 5-FU. Repeated administra-
tion of 5-FU increases the expression of thymidylate synthase
(TS) and consequently activates NF-κB, which results in resistance to
5-Fu in breast cancer cells. Research has shown that concomitant use
of curcumin and 5-Fu downregulates TS and inactivates NF-κB,
thereby improved the therapeutic effect of 5-FU (Tan &
Norhaizan, 2019; Vinod et al., 2013). Falah et al. studied the combina-
tion of metformin and curcumin against breast cancer in mice. They
suggested the combination of metformin and curcumin showed the
highest effect against cell proliferation in vitro and tumor growth
in vivo. The action of curcumin against angiogenesis was augmented
by its combination with metformin. Moreover, the combination
showed the highest effect on necrosis enhancement and apoptosis
induction. It is also safe and did not exhibit toxicity side effects
against liver and kidney functions (Falah, Talib, & Shbailat, 2017).
It has been seen that curcumin increases the sensitivity of the
colon cells to vincristine, cisplatin, and fluorouracil by inhibiting P-gp
and MDR (Lee, Joung, Cho, Son, & Lee, 2018). 5-FU, oxaliplatin, and
irinotecan are common drugs for the treatment of colone cancer that
generally, the efflux of these drugs from the cells by ABC transporters
reduces their effectiveness. Curcumin has been shown to suppress P-
of these drugs in the colon cancer cells (Hu, Li, Gao, & Cho, 2016). In
addition, it has significantly removed 5-FU resistance in HCT-8 cell
line through downregulation of P-gp and HSP-27 and with reduction
in survivin and Bcl-2 expression induced apoptosis in these cells (Fan,
Abulimiti, Zhang, Zhou, & Zhu, 2017). Another finding has shown pre-
treatment of HCT116R cells with curcumin effectively reduced the
5-fu resistance in resistant MMR deficient cells (Shakibaei
et al., 2014). Combination of camptothecin and curcumin-loaded cat-
ionic polymeric nanoparticle increased intracellular drug concentra-
tions and synergistic effects of the drugs in the colon-26 cells (Tan &
Norhaizan, 2019). Studies have shown that curcumin inhibits prolifer-
ation of colon cancer by suppressing NF-κB activity and down-
regulation of COX −2. In addition, inhibiting NF-κB blocks the
expression of MMP-9 and prevents invasion and metastasis of cancer
cells (Park, 2010). One of the reasons for the development of
irinotecan resistance is EMT in colon cancer. Research has shown that
curcumin significantly reduces irinotecan resistance and inhibits cell
proliferation by increasing E-cadherin expression and decreasing
vimentin and N-cadherin expression, which are responsible proteins
for the EMT process. Thus, curcumin increases the sensitivity of the
colon cancer cells to irinotecan and induces apoptosis by removing
the EMT process (Zhang et al., 2018).
Curcumin could inhibited transcription of HPV 16 E6/E7,
upregulated p53, Rb, and PTPN13 expression in cervical cancer cells
KEYVANI-GHAMSARI ET AL.
(Mishra & Das, 2015). Other authors have also reported that
coadministration of curcumin and paclitaxel has a synergistic effect on
the treatment of cervical cancer. Curcumin increased susceptibility of
cervical cancer cells to paclitaxel via downregulation of NF-κB and
Akt, increasing expression of p53, activating caspase 3, -7, -8, and -9,
and release of cytochrome c (Bava et al., 2011; Dang, Yuan, Tian, Li, &
Liu, 2015; Wei et al., 2017). Curcumin by downregulation of HDACs,
induced acetylation of p53 and overexpressed p53 in the cervical can-
cer cell line SiHa and a drug-resistant clone SiHaR, lead to cell cycle
arrest in phase G1-S. In addition, it reversed the drug resistance of
cervical cancer cells to cisplatin by suppression of MRP1 and P-gp1,
therefore cells need a lower dose of drug (Roy & Mukherjee, 2014;
Figure 10).
In vitro and in vivo studies have demonstrated that curcumin has
toxic effect on doxorubicin-resistant melanoma cells and induces apo-
ptosis in them (Odot et al., 2004). In A375 and C8161 cells, it arrested
cells at G2/M phase, and suppressed cell invasion via downregulation
PI3K/AKT/mTOR/P70S6K signaling pathway (ZHAO et al., 2016).
Another study has shown the combination of curcumin and tamoxifen
at low doses induces apoptosis in the melanoma drug-resistant cells
by increasing of ROS generation. In addition, it significantly induced
autophagy in the cancer cells. Importantly, this combination does not
affect noncancerous cells (Chatterjee & Pandey, 2011). Curcumin
decreased ethoposide resistance in melanoma cells by decreasing
MPR1 and GST expression (Depeille, Cuq, Passagne, Evrard, &
Vian, 2005).
Studies have shown that combination of cisplatin with curcumin
enhances the effectiveness of cisplatin in lung cancer cell lines. The
combined reduced cyclin D1 expression, increased p21 expression
F I G U R E 1 0 Co-treatment with curcumin and chemotherapy drugs. Curcumin increases chemosensitivity of anticancer drugs by changing
different signaling pathway. Reproduced with permission from Tan and Norhaizan (2019) [Colour figure can be viewed at wileyonlinelibrary.com]
15
and thereby activated APAF-1 and caspase-9, which increased apo-
ptosis induction in cancer cells (Baharuddin et al., 2016). One of the
reasons for cisplatin resistance is related to the level of copper trans-
porter 1 (CTR1) at the cell surface, which plays a key role in platinum
uptake. The amount of CTR1 is inversely related to the amount of
copper in the cells. The researches illustrated curcumin can act as a
copper chelating agent, thus increasing the expression of CTR1 and
enhancing the absorption of cisplatin in the non-small-cell lung cancer
(NSCLC), thereby increasing the sensitivity of tumor cells to cisplatin
in vivo and in vitro (Zhang et al., 2018). Another study has proved that
curcumin enhances the toxicity of gefitinib in NSCLC by down-
regulating EGFR protein. Combination of curcumin with gefitinib also
inhibits Sp1, which reduces the expression of Sp1-dependent pro-
teins, such as survivin, VEGF, and c-Met, in a manner that strongly
inhibits the growth of primary resistant NSCLC cells and can induce
autophagy and apoptosis in the cells (Chen et al., 2019). in vivo and
in vitro studies have shown curcumin inhibits angiogenesis by block-
ing PI3K/Akt/mTOR signaling pathway, inhibits hepatocyte growth
factor-induced migration and induces apoptosis in lung cancer cells. In
the experimental mouse model, curcumin increased the expression of
E-cadherin and downregulated the expression of vimentin, CD34, and
VEGF and thereby inhibited EMT (Jiao et al., 2016).
Peng et al. reported overexpression of P-gp in imatinib-resistant
K562 cells (Peng, Tiwari, Wu, & Chen, 2012). Curcumin enhanced the
sensitivity of K562 cells to this drug by downregulation of P-gp. Also,
combination of curcumin and imatinib increased apoptosis induction
in the cells by reducing expression of NF-κB, surviving, HSP90, Bcl2
genes and increasing caspase activity (Mukherjee, Sarkar, Mukherjee,
Biswas, & Roy, 2016; Peng et al., 2012).
16
5 | C U R CU M I N I N C LI NI CA L TR I A L S
The first clinical use of curcumin carried out in 1937 against cholecys-
titis, but its clinical trial alone or in combination with other compounds
has been widely done for about a quarter of a century against various
cancers. Its use has been approved in many parts of the world, and as
mentioned, various types of delivery systems have been designed to
increase its bioavailability (Shanmugam et al., 2015). Pharmacological
effects of curcumin as oral formulation in a dose-finding design were
explored in 15 patients who had advanced colorectal cancer resistant
to chemotherapy. Patients received doses of 0.45–3.6 g daily for
approximately 4 months. Curcumin levels and its metabolites were
measured in plasma, urine, and feces. Also, the level of glutathione S-
transferase activity and prostaglandin E2 (PGE2) production in blood
were measured as biomarkers of curcumin activity. Dose-limiting tox-
icity was not seen. The concentration of 10 nmol/L of curcumin and
its glucuronide and sulfate metabolites were observed in plasma and
in urine. The daily administration of 3.6 g reduced PGE2 production in
blood samples were collected 1 hr after consumption by 62 and 57%
on Days 1 and 29, respectively. According to the results an oral dose
of 3.6 g/day was proposed is suitable for the Phase II trial to prevent
or treat outside the gastrointestinal tract (Sharma et al., 2004).
Another study in a Phase I clinical trial showed that administration of
3.6 mg curcumin three times daily for 10–30 days reduced serum
tumor necrosis factor alpha (TNF-α) levels in patients with colon can-
cer. On the other hand, enhanced P53 and Bax expression in tumor
tissues, thereby increased apoptosis in tumor cells (He et al., 2011).
Bayet-Robert et al. in a Phase I clinical trial in 14 patients with
advanced and metastatic breast cancer evaluated the combination of
docetaxel 100 mg/m2 every 3 weeks during six cycles of chemother-
apy with curcumin 0.5–8 g/day for seven consecutive days per cycle.
A partial response was seen in some patients, but no progress was
observed in any patients. The authors suggested that inhibition of
cancer progression can be due to the effect of curcumin on down-
regulation of P-gp that increased docetaxel absorption and removed
the resistance of cells to it. VEGF levels reduced significantly after
three cycles of treatment. The results suggested that the best tolera-
ble dose of curcumin can be 6 g/day in combination with a standard
dose of docetaxel for Phase II clinical trials. (Bayet-Robert
et al., 2010). Another study was conducted on theracurmin (a new
form of curcumin) in pancreatic cancer. The 16 patients took
theracurmin daily with standard gemcitabine concentration for
6 months. The results provided safety and high bioavailability of
theracurmin. The quality of life of patients also increased. No signifi-
cant changes in NF-κB activity and cytokine levels were observed
(Kanai et al., 2013). Greil et al. investigated the safety and pharmaco-
logical effect of liposomal curcumin on patients with metastatic can-
cers. Liposomal curcumin was given by intravenous injection to
32 patients. Its increasing dose started from 100 mg/m2 over 8 hr to
300 mg/m2 over 6 hr. During injection curcumin concentration in
plasma was constant but declined rapidly after injection. Drug toxicity
was not reported in doses of 100–300 mg/m2 over 8 hr in 26 patients.
Of the six patients who were given 300 mg/m2 over 6 hr, one patient
KEYVANI-GHAMSARI ET AL.
experienced hemolysis and three patients experienced significantly
reduced hemoglobin (Greil et al., 2018). Other researcher was con-
ducted in Phase II trial of curcumin in the pancreatic cancer. For this
purpose, 25 patients received 8 g/day of curcumin orally as their dis-
ease progressed with a break of 2 months. Analysis of curcumin phar-
macology suggested low bioavailability of curcumin was improved.
The toxicity of the drug was not seen. Two patients responded to
treatment, and one patient was stable for more than 18 months and
another patient showed brief tumor response. The expression of NF-
κB, COX-2, and pSTAT3 reduced in peripheral blood mononuclear
cells of patients (Dhillon et al., 2008). In another study, Phase I/II trial,
the effect of combination of curcumin with gemcitabine was evalu-
ated in gemcitabine-resistant pancreatic cancer patients. The
21 patients were given 8 g of curcumin orally every day plus a stan-
dard dose of gemcitabine. Since no toxicity was seen in patients in
Phase I, the same drug concentration was selected for the Phase II
study. Outcome was safe and well tolerated in all patients in this
study. Median survival time was 161 days. Further studies are needed
to complete the results on this satisfactory combination (Kanai
et al., 2011). Thus clinical results have shown that curcumin alone or
in combination with other drugs even up to the concentration of 8 g/
day is safe, tolerable and without side effects in normal cells in various
cancers. However, its bioavailability is still a problem and the use of
curcumin analogues and its delivery systems are in the early stages.
Nevertheless, curcumin has been introduced as a promising com-
pound in the treatment of cancer (Shanmugam et al., 2015).
6 | CONC LU SION
Despite significant advances in the production of new chemotherapy
drugs, cancer treatment generally fails due to drug resistance. Drug
resistance is caused by multiple mechanisms such as drug efflux, DNA
repair, drug inactivation or its target alteration, apoptosis breakdown,
and epigenetic changes (Housman et al., 2014; Klopfleisch
et al., 2016). Nevertheless, combination therapy can be the best
approach compared with the monotherapy to reduce the factors caus-
ing resistance (Mokhtari et al., 2017). As we described in this review,
curcumin has a significant effect on the cancer prevention, inhibiting
cancer progression, induction of apoptosis, and by various mecha-
nisms removes the drug resistance and enhances efficacy of chemo-
therapy. Curcumin modulates signaling pathways of immune system,
cell cycle, apoptosis, metastasis, angiogenesis in the cells by regulating
the expression of proteins such as oncogenes, tumor suppressor
genes, pro- and antiapoptotic proteins, NF-κB, Akt, VEGF, STAT3,
MAPKs, COX-2, EGFR, HER-2, check points of the cell cycle, and
MAPK (Rahmani, Al Zohairy, Aly, & Khan, 2014; Tomeh et al., 2019;
Wei et al., 2017). Numerous articles have reported curcumin-based
inhibition of ABC transporters, DNA repair proteins, DNMTs, HDACs,
activation of apoptotic genes, and regulating regulation of the expres-
sion of metabolic enzymes which overcomes the drug resistance and
increases chemosensitivity in various types of cancers both in vitro
and in vivo (Hsieh et al., 2014; Ismail, Othman, Abas, Lajis, &
KEYVANI-GHAMSARI ET AL.
Naidu, 2019; Limtrakul et al., 2004; Liu et al., 2009; Lu et al., 2009;
Reuter et al., 2011). Despite the high efficacy of curcumin in the treat-
ment of cancer, its low toxicity and high safety, its main problem is
poor water solubility, low stability, and low bioavailability. To over-
come this problem strategies such as structural modifications and cur-
cumin nanoformulations have been devised to increase the uptake
and stability of curcumin (Khorsandi et al., 2015, 2019; Rai
et al., 2015; Tan & Norhaizan, 2019; Tomeh et al., 2019).
Therefore, understanding the function and mechanism of cur-
cumin, and the most appropriate way to enhance its bioavailability
provide insights into how to use this powerful natural agent to
enhance the effectiveness of antitumor drugs.
CONF LICT OF IN TE RE ST
The authors declare no conflict of interest.
ORCID
Khatereh Khorsandi https://orcid.org/0000-0001-6882-5031
RE FE R ENC E S
Aggarwal, S., Takada, Y., Singh, S., Myers, J. N., & Aggarwal, B. B. (2004).
Inhibition of growth and survival of human head and neck squamous
cell carcinoma cells by curcumin via modulation of nuclear factor-κB
signaling. International Journal of Cancer, 111, 679–692. https://doi.
org/10.1002/ijc.20333
Alfarouk, K. O., Stock, C. M., Taylor, S., Walsh, M., Muddathir, A. K.,
Verduzco, D., … Rauch, C. (2015). Resistance to cancer chemotherapy:
Failure in drug response from ADME to P-gp. Cancer Cell International,
15, 1–13. https://doi.org/10.1186/s12935-015-0221-1
Ali, S., Ahmad, A., Banerjee, S., Padhye, S., Dominiak, K., Schaffert, J. M., …
Sarkar, F. H. (2010). Gemcitabine sensitivity can be induced in pancre-
atic cancer cells through modulation of miR-200 and miR-21 expres-
sion by curcumin or its analogue CDF. Cancer Research, 70,
3606–3617. https://doi.org/10.1158/0008-5472.CAN-09-4598
Allocati, N., Masulli, M., Di Ilio, C., & Federici, L. (2018). Glutathione trans-
ferases: Substrates, inihibitors and pro-drugs in cancer and neurode-
generative diseases. Oncogene, 7, 8. https://doi.org/10.1038/s41389-
017-0025-3
Ambudkar, S. V., Kimchi-Sarfaty, C., Sauna, Z. E., & Gottesman, M. M.
(2003). P-glycoprotein: From genomics to mechanism. Oncogene, 22,
7468–7485. https://doi.org/10.1038/sj.onc.1206948
Aslam, M. S., Naveed, S., Ahmed, A., Abbas, Z., Gull, I., & Athar, M. A.
(2014). Side effects of chemotherapy in cancer patients and evaluation
of patients opinion about starvation based differential chemotherapy.
Journal of Cancer Therapy, 05, 817–822. https://doi.org/10.4236/jct.
2014.58089
Aung, T., Qu, Z., Kortschak, R., & Adelson, D. (2017). Understanding the
effectiveness of natural compound mixtures in Cancer through their
molecular mode of action. International Journal of Molecular Sciences,
18, 656. https://doi.org/10.3390/ijms18030656
Baharuddin, P., Satar, N., Fakiruddin, K. S., Zakaria, N., Lim, M. N.,
Yusoff, N. M., … Yahaya, B. H. (2016). Curcumin improves the efficacy
of cisplatin by targeting cancer stem-like cells through p21 and cyclin
D1-mediated tumour cell inhibition in non-small cell lung cancer cell
lines. Oncology Reports, 35, 13–25. https://doi.org/10.3892/or.2015.
4371
Baig, S., Seevasant, I., Mohamad, J., Mukheem, A., Huri, H. Z., &
Kamarul, T. (2016). Potential of apoptotic pathway-targeted cancer
therapeutic research: Where do we stand? Cell Death & Disease, 7,
e2058. https://doi.org/10.1038/cddis.2015.275
17
Baker, E. K., & El-Osta, A. (2003). The rise of DNA methylation and the
importance of chromatin on multidrug resistance in cancer. Experimen-
tal Cell Research, 290, 177–194. https://doi.org/10.1016/S0014-4827
(03)00342-2
Bava, S. V., Sreekanth, C. N., Thulasidasan, A. K. T., Anto, N. P.,
Cheriyan, V. T., Puliyappadamba, V. T., … Anto, R. J. (2011). Akt is
upstream and MAPKs are downstream of NF-κB in paclitaxel-induced
survival signaling events, which are down-regulated by curcumin con-
tributing to their synergism. The International Journal of Biochemistry &
Cell Biology, 43, 331–341. https://doi.org/10.1016/j.biocel.2010.
09.011
Bayet-Robert, M., Kwiatkowski, F., Leheurteur, M., Gachon, F.,
Planchat, E., Abrial, C., … Chollet, P. (2010). Phase I dose escalation
trial of docetaxel plus curcumin in patients with advanced and meta-
static breast cancer. Cancer Biology & Therapy, 9, 14. https://doi.org/
10.4161/cbt.9.1.10392
Bell, D. W., Gore, I., Okimoto, R. A., Godin-Heymann, N., Sordella, R.,
Mulloy, R., … Haber, D. A. (2005). Inherited susceptibility to lung can-
cer may be associated with the T790M drug resistance mutation in
EGFR. Nature Genetics, 37, 1315–1316. https://doi.org/10.1038/
ng1671
Bibi, Z. (2008). Nutrition & metabolism role of cytochrome P450 in drug
interactions. Nutrition & Metabolism (London), 5, 1–10. https://doi.org/
10.1186/1743-7075-5-27
Bora-Tatar, G., Dayangaç-Erden, D., Demir, A. S., Dalkara, S., Yelekçi, K., &
Erdem-Yurter, H. (2009). Molecular modifications on carboxylic acid
derivatives as potent histone deacetylase inhibitors: Activity and dock-
ing studies. Bioorganic & Medicinal Chemistry, 17, 5219–5228. https://
doi.org/10.1016/j.bmc.2009.05.042
Boyanapalli, S. S. S., & Kong, A. N. T. (2015). “Curcumin, the king of
spices”: Epigenetic regulatory mechanisms in the prevention of cancer,
neurological, and inflammatory diseases. Current Pharmacology Reports,
1, 129–139. https://doi.org/10.1007/s40495-015-0018-x
Boyer, J., McLean, E. G., Aroori, S., Wilson, P., McCulla, A., Carey, P. D., …
Johnston, P. G. (2004). Characterization of p53 wild-type and null iso-
genic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin,
and irinotecan. Clinical Cancer Research, 10, 2158–2167. https://doi.
org/10.1158/1078-0432.CCR-03-0362
Bozic, I., Reiter, J. G., Allen, B., Antal, T., Chatterjee, K., Shah, P., …
Nowak, M. A. (2013). Evolutionary dynamics of cancer in response to
targeted combination therapy. eLife, 2013, 1–15. https://doi.org/10.
7554/eLife.00747
Chan, H.-K., & Ismail, S. (2014). Side effects of chemotherapy among can-
cer patients in a Malaysian general hospital: Experiences, perceptions
and informational needs from clinical pharmacists. Asian Pacific Journal
of Cancer Prevention, 15, 5305–5309. https://doi.org/10.7314/apjcp.
2014.15.13.5305
Chang, G. (2003). Multidrug resistance ABC transporters. FEBS Letters,
555, 102–105. https://doi.org/10.1016/S0014-5793(03)01085-8
Chatterjee, S. J., & Pandey, S. (2011). Chemo-resistant melanoma sensi-
tized by tamoxifen to low dose curcumin treatment through induction
of apoptosis and autophagy. Cancer Biology & Therapy, 11, 216–228.
https://doi.org/10.4161/cbt.11.2.13798
Chearwae, W., Shukla, S., Limtrakul, P., & Ambudkar, S. V. (2006). Modula-
tion of the function of the multidrug resistance-linked ATP-binding
cassette transporter ABCG2 by the cancer chemopreventive agent
curcumin. Molecular Cancer Therapeutics, 5, 1995–2006. https://doi.
org/10.1158/1535-7163.MCT-06-0087
Chen, P., Huang, H. P., Wang, Y., Jin, J., Long, W. G., Chen, K., … Li, J.
(2019). Curcumin overcome primary gefitinib resistance in non-small-
cell lung cancer cells through inducing autophagy-related cell death.
Journal of Experimental & Clinical Cancer Research, 38, 1–17. https://
doi.org/10.1186/s13046-019-1234-8
Conseil, G., Baubichon-Cortay, H., Dayan, G., Jault, J.-M., Barron, D., & Di
Pietro, A. (2002). Flavonoids: A class of modulators with bifunctional
18
interactions at vicinal ATP- and steroid-binding sites on mouse P-gly-
coprotein. Proceedings of the National Academy of Sciences of the
United States of America, 95, 9831–9836. https://doi.org/10.1073/
pnas.95.17.9831
Couleaud, P., Morosini, V., Frochot, C., Richeter, S., Raehm, L., &
Durand, J.-O. (2010). Silica-based nanoparticles for photodynamic
therapy applications. Nanoscale, 2, 1083–1095. https://doi.org/10.
1039/c0nr00096e
Criscitiello, C., Fumagalli, D., Saini, K. S., & Loi, S. (2011). Tamoxifen in
early-stage estrogen receptor positive breast cancer: Overview of clin-
ical use and molecular biomarkers for patient selection. Oncotargets
and Therapy, 4, 1–11. https://doi.org/10.2147/OTT.S10155
Dang, Y. P., Yuan, X. Y., Tian, R., Li, D. G., & Liu, W. (2015). Curcumin
improves the paclitaxel induced apoptosis of HPV positive human cer-
vical cancer cells via the NF κB p53 caspase 3 pathway. Experimental
and Therapeutic Medicine, 9, 1470–1476. https://doi.org/10.3892/
etm.2015.2240
Danielson, P. B. (2002). The cytochrome P450 superfamily: Biochemistry,
evolution and drug metabolism in humans. Current Drug Metabolism, 3,
561–597. https://doi.org/10.2174/1389200023337054
De, A., Beligala, D. H., Birkholz, T. M., & Geusz, M. E. (2019). Anticancer
properties of curcumin and interactions with the circadian timing sys-
tem. Integrative Cancer Therapies, 18, 1–10. https://doi.org/10.1177/
1534735419889154
de Vries, E. G. E. (2006). Tumor necrosis factor-related apoptosis-inducing
ligand pathway and its therapeutic implications. Clinical Cancer
Research, 12, 2390–2393. https://doi.org/10.1158/1078-0432.CCR-
06-0352
Depeille, P., Cuq, P., Passagne, I., Evrard, A., & Vian, L. (2005). Combined
effects of GSTP1 and MRP1 in melanoma drug resistance. British Jour-
nal of Cancer, 93(2), 216–223. https://doi.org/10.1038/sj.bjc.6602681
Dhillon, N., Aggarwal, B. B., Newman, R. A., Wolff, R. A.,
Kunnumakkara, A. B., Abbruzzese, J. L., … Kurzrock, R. (2008). Phase II
trial of curcumin in patients with advanced pancreatic cancer. Clinical
Cancer Research, 14, 4491–4499. https://doi.org/10.1158/1078-
0432.CCR-08-0024
Duvoix, A., Morceau, F., Delhalle, S., Schmitz, M., Schnekenburger, M.,
Galteau, M. M., … Diederich, M. (2003). Induction of apoptosis by cur-
cumin: Mediation by glutathione S-transferase P1-1 inhibition. Bio-
chemical Pharmacology, 66, 1475–1483. https://doi.org/10.1016/
S0006-2952(03)00501-X
Eid, S. Y., El-Readi, M. Z., Fatani, S. H., Mohamed Nour Eldin, E. E., &
Wink, M. (2015). Natural products modulate the multifactorial
multidrug resistance of cancer. Journal of Pharmacy and Pharmacology,
06, 146–176. https://doi.org/10.4236/pp.2015.63017
Ekor, M. (2014). The growing use of herbal medicines: Issues relating to
adverse reactions and challenges in monitoring safety. Frontiers in Neu-
rology, 4, 1–10. https://doi.org/10.3389/fphar.2013.00177
Escárcega, R. O., Fuentes-Alexandro, S., García-Carrasco, M., Gatica, A., &
Zamora, A. (2007). The transcription factor nuclear factor-kappa B and
cancer. Clinical Oncology, 19, 154–161. https://doi.org/10.1016/j.clon.
2006.11.013
Fabian, M. R., Sonenberg, N., & Filipowicz, W. (2010). Regulation of mRNA
translation and stability by microRNAs. Annual Review of Biochemistry,
79, 351–379. https://doi.org/10.1146/annurev-biochem-060308-
103103
Falah, R. R., Talib, W. H., & Shbailat, S. J. (2017). Combination of metfor-
min and curcumin targets breast cancer in mice by angiogenesis inhibi-
tion, immune system modulation and induction of p53 independent
apoptosis. Therapeutic Advances in Medical Oncology, 9, 235–252.
https://doi.org/10.1177/1758834016687482
Fan, Y. X., Abulimiti, P., Zhang, H. L., Zhou, Y. K., & Zhu, L. (2017). Mecha-
nism of reversal of multidrug resistance by curcumin in human colorec-
tal cancer cell line HCT-8/5-FU. Genetics and Molecular Research, 16,
1–13. https://doi.org/10.4238/gmr16029414
KEYVANI-GHAMSARI ET AL.
Fardi, M., Solali, S., & Farshdousti Hagh, M. (2018). Epigenetic mechanisms
as a new approach in cancer treatment: An updated review. Genes &
Diseases, 5, 304–311. https://doi.org/10.1016/j.gendis.2018.06.003
Fulda, S., & Debatin, K.-M. (2006). Extrinsic versus intrinsic apoptosis path-
ways in anticancer chemotherapy. Oncogene, 25, 4798–4811. https://
doi.org/10.1038/sj.onc.1209608
Ganta, S., & Amiji, M. (2009). Coadministration of paclitaxel and curcumin
in nanoemulsion formulations to overcome multidrug resistance in
tumor cells. Molecular Pharmaceutics, 6, 928–939. https://doi.org/10.
1021/mp800240j
Garc, M., Elisabet, P., & Redondo, M. 2018. Bcl-2 inhibition to overcome
resistance to chemo- and immunotherapy. doi:https://doi.org/10.
3390/ijms19123950
García-Becerra, R., Santos, N., Díaz, L., & Camacho, J. (2013). Mechanisms
of resistance to endocrine therapy in breast cancer: Focus on signaling
pathways, miRNAs and genetically based resistance. International Jour-
nal of Molecular Sciences, 14, 108–145. https://doi.org/10.3390/
ijms14010108
Geisler, S., Børresen-Dale, A. L., Johnsen, H., Aas, T., Geisler, J.,
Akslen, L. A., … Lønning, P. E. (2003). TP53 gene mutations predict the
response to neoadjuvant treatment with 5-fluorouracil and mitomycin
in locally advanced breast cancer. Clinical Cancer Research, 9,
5582–5588.
Ghasabi, M., Mansoori, B., Mohammadi, A., Duijf, P. H. G., Shomali, N.,
Shirafkan, N., … Baradaran, B. (2019). MicroRNAs in cancer drug resis-
tance: Basic evidence and clinical applications. Journal of Cellular Physi-
ology, 234, 2152–2168. https://doi.org/10.1002/jcp.26810
Goel, A., & Aggarwal, B. B. (2010). Curcumin, the Golden spice from Indian
saffron, is a chemosensitizer and radiosensitizer for tumors and
chemoprotector and radioprotector for normal organs. Nutrition and Can-
cer, 62, 919–930. https://doi.org/10.1080/01635581.2010.509835
Greil, R., Greil-Ressler, S., Weiss, L., Schönlieb, C., Magnes, T., Radl, B., …
Sordillo, P. P. (2018). A phase 1 dose-escalation study on the safety,
tolerability and activity of liposomal curcumin (Lipocurc™) in patients
with locally advanced or metastatic cancer. Cancer Chemotherapy and
Pharmacology, 82, 695–706. https://doi.org/10.1007/s00280-018-
3654-0
Hamed, A. R., Abdel-Azim, N. S., Shams, K. A., & Hammouda, F. M. (2019).
Targeting multidrug resistance in cancer by natural chemosensitizers.
Bulletin of the National Research Centre, 43, 8. https://doi.org/10.
1186/s42269-019-0043-8
Hassan, F., Rehman, M. S., Khan, M. S., Ali, M. A., Javed, A., Nawaz, A., &
Yang, C. (2019). Curcumin as an alternative epigenetic modulator:
Mechanism of action and potential effects. Frontiers in Genetics, 10,
514. https://doi.org/10.3389/fgene.2019.00514
He, Y., Li, W., Hu, G., Sun, H., & Kong, Q. (2018). Bioactivities of EF24, a
novel curcumin analog: A review. Frontiers in Oncology, 8, 614. https://
doi.org/10.3389/fonc.2018.00614
He, Z. Y., Shi, C. B., Wen, H., Li, F. L., Wang, B. L., & Wang, J. (2011).
Upregulation of p53 expression in patients with colorectal cancer by
administration of curcumin. Cancer Investigation, 29, 208–213. https://
doi.org/10.3109/07357907.2010.550592
Hervouet, E., Cartron, P., Jouvenot, M., & Delage-mourroux, R. (2013). Epi-
genetic regulation of estrogen signaling in breast cancer. Epigenetics,
2013, 237–245.
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G.
(2013). Cancer drug resistance: An evolving paradigm. Nature Reviews.
Cancer, 13, 714–726. https://doi.org/10.1038/nrc3599
Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., &
Sarkar, S. (2014). Drug resistance in cancer: An overview. Cancers (Basel).,
6, 1769–1792. https://doi.org/10.3390/cancers6031769
Hsieh, Y. W., Huang, C. Y., Yang, S. Y., Peng, Y. H., Yu, C. P.,
Chao, P. D. L., & Hou, Y. C. (2014). Oral intake of curcumin markedly
activated CYP 3A4: in vivo and ex-vivo studies. Scientific Reports, 4,
1–7. https://doi.org/10.1038/srep06587
KEYVANI-GHAMSARI ET AL.
Hu, Q., & Baeg, G. H. (2017). Role of epigenome in tumorigenesis and drug
resistance. Food and Chemical Toxicology, 109, 663–668. https://doi.
org/10.1016/j.fct.2017.07.022
Hu, T., Li, Z., Gao, C. Y., & Cho, C. H. (2016). Mechanisms of drug resis-
tance in colon cancer and its therapeutic strategies. World Journal of
Gastroenterology, 22, 6876–6889. https://doi.org/10.3748/wjg.v22.
i30.6876
Huang, C.-Y., Ju, D.-T., Chang, C.-F., Muralidhar Reddy, P., &
Velmurugan, B. K. (2017). A review on the effects of current chemo-
therapy drugs and natural agents in treating non-small cell lung cancer.
Biomedicine, 7, 23. https://doi.org/10.1051/bmdcn/2017070423
Iqbal, J., Abbasi, B. A., Mahmood, T., Kanwal, S., Ali, B., Shah, S. A., &
Khalil, A. T. (2017). Plant-derived anticancer agents: A green antican-
cer approach. Asian Pacific Journal of Tropical Biomedicine, 7,
1129–1150. https://doi.org/10.1016/j.apjtb.2017.10.016
Ismail, N. I., Othman, I., Abas, F., Lajis, N. H., & Naidu, R. (2019). Mecha-
nism of apoptosis induced by curcumin in colorectal cancer. Interna-
tional Journal of Molecular Sciences, 20, 2454. https://doi.org/10.
3390/ijms20102454
Jacob, A., Wu, R., Zhou, M., & Wang, P. (2007). Mechanism of the anti-
inflammatory effect of curcumin: PPAR-γ activation. PPAR Research,
2007, 1–5. https://doi.org/10.1155/2007/89369
Jalkanen, A. L., Coleman, S. J., & Wilusz, J. (2014). Determinants and impli-
cations of mRNA poly(A) tail size—Does this protein make my tail look
big? Seminars in Cell & Developmental Biology, 34, 24–32. https://doi.
org/10.1016/j.semcdb.2014.05.018
Ji, Z. (2010). Targeting DNA damage and repair by curcumin. Breast cancer:
Basic and Clinical Research, 4, 3–5.
Jiao, D., Wang, J., Lu, W., Tang, X., Chen, J., Mou, H., & Chen, Q. Y. (2016).
Curcumin inhibited HGF-induced EMT and angiogenesis through regu-
lating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung
cancer. Molecular Therapy: Oncolytics, 3, 16018. https://doi.org/10.
1038/mto.2016.18
Jubierre, L., Jiménez, C., Rovira, E., Soriano, A., Sábado, C., Gros, L., …
Segura, M. F. (2018). Targeting of epigenetic regulators in neuroblas-
toma. Experimental & Molecular Medicine, 50, 51. https://doi.org/10.
1038/s12276-018-0077-2
Kanai, M., Otsuka, Y., Otsuka, K., Sato, M., Nishimura, T., Mori, Y., …
Shibata, H. (2013). A phase i study investigating the safety and phar-
macokinetics of highly bioavailable curcumin (Theracurmin®) in cancer
patients. Cancer Chemotherapy and Pharmacology, 71, 1521–1530.
https://doi.org/10.1007/s00280-013-2151-8
Kanai, M., Yoshimura, K., Asada, M., Imaizumi, A., Suzuki, C.,
Matsumoto, S., … Aggarwal, B. B. (2011). A phase I/II study of
gemcitabine-based chemotherapy plus curcumin for patients with
gemcitabine-resistant pancreatic cancer. Cancer Chemotherapy and
Pharmacology, 68, 157–164. https://doi.org/10.1007/s00280-010-
1470-2
Kanwal, R., & Gupta, S. (2012). Epigenetic modifications in cancer. Clinical
Genetics, 81, 303–311. https://doi.org/10.1111/j.1399-0004.2011.
01809.x
Kanwar, S. S., Yu, Y., Nautiyal, J., Patel, B. B., Padhye, S., Sarkar, F. H., &
Majumdar, A. P. N. (2011). Difluorinated-curcumin (CDF): A novel cur-
cumin analog is a potent inhibitor of colon cancer stem-like cells. Phar-
maceutical Research, 28, 827–838. https://doi.org/10.1007/s11095-
010-0336-y
Khazaei Koohpar, Z., Entezari, M., Movafagh, A., & Hashemi, M. (2015).
Anticancer activity of curcumin on human breast adenocarcinoma:
Role of Mcl-1 gene. Iranian Journal of Cancer Prevention, 8, e2331.
https://doi.org/10.17795/ijcp2331
Khorsandi, K., Hosseinzadeh, R., & Fateh, M. (2015). Curcumin intercalated
layered double hydroxide nanohybrid as a potential drug delivery sys-
tem for effective photodynamic therapy in human breast cancer cells.
RSC Advances, 5, 93987–93994. https://doi.org/10.1039/
C5RA15888E
19
Khorsandi, K., Hosseinzadeh, R., & Shahidi, F. K. (2019). Photodynamic
treatment with anionic nanoclays containing curcumin on human
triple-negative breast cancer cells: Cellular and biochemical studies.
Journal of Cellular Biochemistry, 120, 4998–5009. https://doi.org/10.
1002/jcb.27775
Kitagawa, S., Nabekura, T., & Kamiyama, S. (2004). Inhibition of P-
glycoprotein function by tea catechins in KB-C2 cells. The Journal of
Pharmacy and Pharmacology, 56, 1001–1005. https://doi.org/10.
1211/0022357044003
Klopfleisch, R., Kohn, B., & Gruber, A. D. (2016). Mechanisms of tumour
resistance against chemotherapeutic agents in veterinary oncology.
Veterinary Journal, 207, 63–72. https://doi.org/10.1016/j.tvjl.2015.
06.015
Kovalchuk, O., Filkowski, J., Meservy, J., Ilnytskyy, Y., Tryndyak, V. P.,
Chekhun, V. F., & Pogribny, I. P. (2008). Involvement of microRNA-
451 in resistance of the MCF-7 breast cancer cells to chemotherapeu-
tic drug doxorubicin. Molecular Cancer Therapeutics, 7, 2152–2159.
https://doi.org/10.1158/1535-7163.MCT-08-0021
Krausz, A. E., Adler, B. L., Cabral, V., Navati, M., Doerner, J.,
Charafeddine, R. A., … Friedman, A. J. (2015). Curcumin-encapsulated
nanoparticles as innovative antimicrobial and wound healing agent.
Nanomedicine Nanotechnology. Biologie et Médecine, 11, 195–206.
https://doi.org/10.1016/j.nano.2014.09.004
Kumar, S., Kushwaha, P. P., & Gupta, S. (2019). Emerging targets in cancer
drug resistance. Cancer Drug Resistance. 2, 161–177. https://doi.org/
10.20517/cdr.2018.27
Kwon, Y. (2014). Curcumin as a cancer chemotherapy sensitizing agent.
Journal of Korean Society for Applied Biological Chemistry, 57, 273–280.
https://doi.org/10.1007/s13765-014-4077-1
Lee, G., Joung, J. Y., Cho, J. H., Son, C. G., & Lee, N. (2018). Overcoming P-
glycoprotein-mediated multidrug resistance in colorectal cancer:
Potential reversal agents among herbal medicines. Alternative Medicine,
2018, 9. https://doi.org/10.1155/2018/3412074
Lee, S. J., Krauthauser, C., Maduskuie, V., Fawcett, P. T., Olson, J. M., &
Rajasekaran, S. A. (2011). Curcumin-induced HDAC inhibition and
attenuation of medulloblastoma growth in vitro and in vivo. BMC Can-
cer, 11, 144. https://doi.org/10.1186/1471-2407-11-144
Lehmann, A. R. (2005). Replication of damaged DNA by translesion syn-
thesis in human cells. FEBS Letters, 579, 873–876. https://doi.org/10.
1016/j.febslet.2004.11.029
Li, Y., Kong, D., Wang, Z., & Sarkar, F. H. (2010). Regulation of microRNAs
by natural agents: An emerging field in chemoprevention and chemo-
therapy research. Pharmaceutical Research, 27, 1027–1041. https://
doi.org/10.1007/s11095-010-0105-y
Li, Y., & Zhang, T. (2014). Targeting cancer stem cells by curcumin and clin-
ical applications. Cancer Letters, 346, 197–205. https://doi.org/10.
1016/j.canlet.2014.01.012
Likhite, V. S., Stossi, F., Kim, K., Katzenellenbogen, B. S., &
Katzenellenbogen, J. A. (2006). Kinase-specific phosphorylation of the
estrogen receptor changes receptor interactions with ligand,
deoxyribonucleic acid, and coregulators associated with alterations in
estrogen and tamoxifen activity. Molecular Endocrinology, 20,
3120–3132. https://doi.org/10.1210/me.2006-0068
Limtrakul, P., Anuchapreeda, S., & Buddhasukh, D. (2004). Modulation of
human multidrug-resistance MDR-1 gene by natural. BMC Cancer,
6, 1–6.
Lin, Y. L., Liu, Y. K., Tsai, N. M., Hsieh, J. H., Chen, C. H., Lin, C. M., &
Liao, K. W. (2012). A Lipo-PEG-PEI complex for encapsulating cur-
cumin that enhances its antitumor effects on curcumin-sensitive and
curcumin-resistance cells. Nanomedicine Nanotechnology. Biologie et
Médecine, 8, 318–327. https://doi.org/10.1016/j.nano.2011.06.011
Liu, F. S. (2009). Mechanisms of chemotherapeutic drug resistance in can-
cer therapy—A quick review. Taiwanese Journal of Obstetrics & Gyne-
cology, 48, 239–244. https://doi.org/10.1016/S1028-4559(09)
60296-5
20
Liu, H.-T., & Ho, Y.-S. (2018). Anticancer effect of curcumin on breast can-
cer and stem cells. Food Science and Human Wellness, 7, 134–137.
https://doi.org/10.1016/j.fshw.2018.06.001
Liu, H. L., Chen, Y., Cui, G. H., & Zhou, J. F. (2005). Curcumin, a potent
anti-tumor reagent, is a novel histone deacetylase inhibitor regulating
B-NHL cell line Raji proliferation. Acta Pharmacologica Sinica, 26,
603–609. https://doi.org/10.1111/j.1745-7254.2005.00081.x
Liu, Z., Xie, Z., Jones, W., Pavlovicz, R. E., Liu, S., Yu, J., … Chan, K. K.
(2009). Curcumin is a potent DNA hypomethylation agent. Bioorganic &
Medicinal Chemistry Letters, 19, 706–709. https://doi.org/10.1016/j.
bmcl.2008.12.041
Lu, H. F., Yang, J. S., Lai, K. C., Hsu, S. C., Hsueh, S. C., Chen, Y. L., …
Chung, J. G. (2009). Curcumin-induced DNA damage and inhibited
DNA repair genes expressions in mouse-rat hybrid retina neuroblas-
toma cells ganglion cells (n18). Neurochemical Research, 34,
1491–1497. https://doi.org/10.1007/s11064-009-9936-5
Ma, J., Dong, C., & Ji, C. (2010). MicroRNA and drug resistance. Cancer
Gene Therapy, 17, 523–531. https://doi.org/10.1038/cgt.2010.18
Malhotra, V., & Perry, M. C. (2003). Classical chemotherapy: Mechanisms,
toxicities and the therapeutc window. Cancer Biology & Therapy, 2,
1–3. https://doi.org/10.4161/cbt.199
Mansoori, B., Mohammadi, A., Davudian, S., Shirjang, S., & Baradaran, B.
(2017). The different mechanisms of cancer drug resistance: A brief
review. Advanced Pharmaceutical Bulletin, 7, 339–348. https://doi.org/
10.15171/apb.2017.041
Mapoung, S., Pitchakarn, P., Yodkeeree, S., Ovatlarnporn, C., Sakorn, N., &
Limtrakul, P. (2016). Chemosensitizing effects of synthetic curcumin ana-
logs on human multi-drug resistance leukemic cells. Chemico-Biological
Interactions, 244, 140–148. https://doi.org/10.1016/j.cbi.2015.12.001
Mathew, N., Kalyanasundaram, M., & Balaraman, K. (2006). Glutathione S-
transferase (GST) inhibitors. Expert Opinion on Therapeutic Patents, 16
(4), 431–444.
Mbese, Z., Khwaza, V., & Aderibigbe, B. A. (2019). Curcumin and its deriv-
atives as potential therapeutic agents in prostate, colon and breast
cancers. Molecules, 24, 4386. https://doi.org/10.3390/molecules
24234386
Meiyanto, E., Putri, D. D. P., Susidarti, R. A., Murwanti, R., Sardjiman, S.,
Fitriasari, A., … Kawaichi, M. (2014). Curcumin and its analogues
(PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to
doxorubicin through inhibition of HER2 and NF-kB activation. Asian
Pacific Journal of Cancer Prevention, 15, 179–184. https://doi.org/10.
7314/apjcp.2014.15.1.179
Meng, W., Ze-Fa, L., Hua, T., & Bao-An, C. (2018). Application of alkaloids
in reversing multidrug resistance in human cancers. Chinese Journal of
Natural Medicines, 16, 561–571. https://doi.org/10.1016/S1875-5364
(18)30093-1
Michael, M., & Doherty, M. M. (2005). Tumoral drug metabolism: Over-
view and its implications for cancer therapy. Journal of Clinical Oncol-
ogy, 23, 205–229. https://doi.org/10.1200/JCO.2005.02.120
Miller, T. E., Ghoshal, K., Ramaswamy, B., Roy, S., Datta, J., Shapiro, C. L.,
… Majumder, S. (2008). MicroRNA-221/222 confers tamoxifen resis-
tance in breast cancer by targeting p27Kip1. The Journal of Biological
Chemistry, 283, 29897–29903. https://doi.org/10.1074/jbc.
M804612200
Millimouno, F. M., Dong, J., Yang, L., Li, J., & Li, X. (2014). Targeting apo-
ptosis pathways in cancer and perspectives with natural compounds
from mother nature. Cancer Prevention Research, 7, 1081–1107.
https://doi.org/10.1158/1940-6207.CAPR-14-0136
Mimeault, M., & Batra, S. K. (2011). Potential applications of curcumin and
its novel synthetic analogs and nanotechnology-based formulations in
cancer prevention and therapy. Chinese Medicine, 6, 31. https://doi.
org/10.1186/1749-8546-6-31
Miremadi, A., Oestergaard, M. Z., Pharoah, P. D. P., & Caldas, C. (2007).
Cancer genetics of epigenetic genes. Human Molecular Genetics, 16,
R28–R49. https://doi.org/10.1093/hmg/ddm021
KEYVANI-GHAMSARI ET AL.
Mirzaei, H., Masoudifar, A., Sahebkar, A., Zare, N., Nahand, J. S.,
Rashidi, B., … Jaafari, M. R. (2017). MicroRNA: A novel target of cur-
cumin in cancer therapy. Journal of Cellular Physiology, 233,
3004–3015. https://doi.org/10.1002/jcp.26055
Mirzaei, H., Momeni, F., Saadatpour, L., Sahebkar, A., Goodarzi, M.,
Masoudifar, A., … Jaafari, M. R. (2018). MicroRNA: Relevance to stroke
diagnosis, prognosis, and therapy. Journal of Cellular Physiology, 233,
856–865. https://doi.org/10.1002/jcp.25787
Mirzahosseinipour, M., Khorsandi, K., Hosseinzadeh, R., Ghazaeian, M., &
Shahidi, F. K. (2020). Antimicrobial photodynamic and wound healing
activity of curcumin encapsulated in silica nanoparticles. Pho-
todiagnosis and Photodynamic Therapy, 29, 101639. https://doi.org/10.
1016/j.pdpdt.2019.101639
Mishra, A., & Das, B. C. (2015). Curcumin as an anti-human papillomavirus
and anti-cancer compound. Future Oncology, 11, 2487–2490. https://
doi.org/10.2217/fon.15.166
Misra, R., & Sahoo, S. K. (2011). Coformulation of doxorubicin and cur-
cumin in poly(d,l-lactide-co-glycolide) nanoparticles suppresses the
development of multidrug resistance in K562 cells. Molecular Pharma-
ceutics, 8, 852–866. https://doi.org/10.1021/mp100455h
Mokhtari, R. B., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S.,
Das, B., & Yeger, H. (2017). Combination therapy in combating cancer.
Oncotarget, 8, 38022–38043. https://doi.org/10.18632/oncotarget.
16723
Mondal, S., Bhattacharya, K., & Mandal, C. (2018). Nutritional stress repro-
grams dedifferention in glioblastoma multiforme driven by
PTEN/Wnt/hedgehog axis: A stochastic model of cancer stem cells. Cell
Death Discovery, 4, 110. https://doi.org/10.1038/s41420-018-0126-6
Mori, Y., Tatematsu, K., Koide, A., Sugie, S., Tanaka, T., & Mori, H. (2006).
Modification by curcumin of mutagenic activation of carcinogenic N-
nitrosamines by extrahepatic cytochromes P-450 2B1 and 2E1 in rats.
Cancer Science, 97, 896–904. https://doi.org/10.1111/j.1349-7006.
2006.00261.x
Mortezaee, K., Najafi, M., Farhood, B., Ahmadi, A., Shabeeb, D., &
Musa, A. E. (2019). NF-κB targeting for overcoming tumor resistance
and normal tissues toxicity. Journal of Cellular Physiology, 234,
17187–17204. https://doi.org/10.1002/jcp.28504
Mudduluru, G., George-William, J. N., Muppala, S., Asangani, I. A.,
Kumarswamy, R., Nelson, L. D., & Allgayer, H. (2011). Curcumin regu-
lates miR-21 expression and inhibits invasion and metastasis in colo-
rectal cancer. Bioscience Reports, 31, 185–197. https://doi.org/10.
1042/BSR20100065
Mukherjee, A., Sarkar, R., Mukherjee, S., Biswas, J., & Roy, M. (2016). Cur-
cumin boosts up the efficacy of imatinib mesylate in chronic
myelogenic leukemia cell line K-562 by modulation of various markers.
International Journal of Current Microbiology and Applied Sciences, 5,
240–255. https://doi.org/10.20546/ijcmas.2016.512.026
Müller, M. R., Thomale, J., Rajewsky, M. F., & Seeber, S. (1998). Drug resis-
tance and DNA repair in leukaemia. Multidrug Resistance Cancer, 2,
175–185. https://doi.org/10.1007/978-94-017-2374-9_11
Murakami, M., Ohnuma, S., Fukuda, M., Chufan, E. E., Kudoh, K.,
Kanehara, K., … Unno, M. (2017). Synthetic analogs of curcumin modu-
late the function of multidrug resistance–linked ATP-binding cassette
transporter ABCG2. Drug Metabolism and Disposition, 45, 1166–1177.
https://doi.org/10.1124/dmd.117.076000
Nabekura, T. (2010). Overcoming multidrug resistance in human cancer
cells by natural compounds. Toxins (Basel)., 2, 1207–1224. https://doi.
org/10.3390/toxins2061207
Nabekura, T., Yamaki, T., Ueno, K., & Kitagawa, S. (2008). Inhibition of P-
glycoprotein and multidrug resistance protein 1 by dietary phytochem-
icals. Cancer Chemotherapy and Pharmacology, 62, 867–873. https://
doi.org/10.1007/s00280-007-0676-4
Najafi, M., Mortezaee, K., & Ahadi, R. (2019). Cancer stem cell (a)symme-
try & plasticity: Tumorigenesis and therapy relevance. Life Sciences,
231, 116520. https://doi.org/10.1016/j.lfs.2019.05.076
KEYVANI-GHAMSARI ET AL.
Najafi, M., Mortezaee, K., & Majidpoor, J. (2019). Cancer stem cell (CSC)
resistance drivers. Life Sciences, 234, 116781. https://doi.org/10.
1016/j.lfs.2019.116781
Nami, B., & Wang, Z. (2018). Genetics and expression profile of the tubulin
gene superfamily in breast cancer subtypes and its relation to taxane
resistance. Cancers (Basel), 10, 274. https://doi.org/10.3390/
cancers10080274
Nikolaou, M., Pavlopoulou, A., Georgakilas, A. G., & Kyrodimos, E. (2018).
The challenge of drug resistance in cancer treatment: A current over-
view. Clinical & Experimental Metastasis, 35, 309–318. https://doi.org/
10.1007/s10585-018-9903-0
Nishinaka, T., Ichijo, Y., Ito, M., Kimura, M., Katsuyama, M., Iwata, K., …
Yabe-Nishimura, C. (2007). Curcumin activates human glutathione S-
transferase P1 expression through antioxidant response element. Toxi-
cology Letters, 170, 238–247. https://doi.org/10.1016/j.toxlet.2007.
03.011
Nobili, S., Lippi, D., Witort, E., Donnini, M., Bausi, L., Mini, E., &
Capaccioli, S. (2009). Natural compounds for cancer treatment and
prevention. Pharmacological Research, 59, 365–378. https://doi.org/
10.1016/j.phrs.2009.01.017
Odot, J., Albert, P., Carlier, A., Tarpin, M., Devy, J., & Madoulet, C. (2004).
In vitro and in vivo anti-tumoral effect of curcumin against melanoma
cells. International Journal of Cancer, 111, 381–387. https://doi.org/10.
1002/ijc.20160
Ooko, E., Alsalim, T., Saeed, B., Saeed, M. E. M., Kadioglu, O.,
Abbo, H. S., … Efferth, T. (2016). Modulation of P-glycoprotein
activity by novel synthetic curcumin derivatives in sensitive and
multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.
Toxicology and Applied Pharmacology, 305, 216–233. https://doi.
org/10.1016/j.taap.2016.06.002
Palumbo, M. O., Kavan, P., Miller, W. H., Panasci, L., Assouline, S.,
Johnson, N., … Batist, G. (2013). Systemic cancer therapy: Achieve-
ments and challenges that lie ahead. Frontiers in Pharmacology, 4, 57.
https://doi.org/10.3389/fphar.2013.00057
Pan, S.-T., Li, Z.-L., He, Z.-X., Qiu, J.-X., & Zhou, S.-F. (2016). Molecular
mechanisms for tumour resistance to chemotherapy. Clinical and
Experimental Pharmacology & Physiology, 43, 723–737. https://doi.org/
10.1111/1440-1681.12581
Panda, A. K., Chakraborty, D., Sarkar, I., Khan, T., & Sa, G. (2017). New
insights into therapeutic activity and anticancer properties of cur-
cumin. Journal of Experimental Pharmacology, 9, 31–45. https://doi.
org/10.2147/JEP.S70568
Park, J. (2010). Anti-carcinogenic properties of curcumin on colorectal can-
cer. World Journal of Gastrointestinal Oncology, 2, 169–176. https://
doi.org/10.4251/wjgo.v2.i4.169
Pathania, S., Bhatia, R., Baldi, A., Singh, R., & Rawal, R. K. (2018). Drug
metabolizing enzymes and their inhibitors' role in cancer resistance.
Biomedicine & Pharmacotherapy, 105, 53–65. https://doi.org/10.1016/
j.biopha.2018.05.117
Peng, X. X., Tiwari, A. K., Wu, H. C., & Chen, Z. S. (2012). Overexpression
of P-glycoprotein induces acquired resistance to imatinib in chronic
myelogenous leukemia cells. Chinese Journal of Cancer, 31, 110–118.
https://doi.org/10.5732/cjc.011.10327
Pfeffer, C. M., & Singh, A. T. K. (2018). Apoptosis: A target for anticancer
therapy. International Journal of Molecular Sciences, 19, 448. https://
doi.org/10.3390/ijms19020448
Pommier, Y. (2013). Drugging topoisomerases: Lessons and challenges.
ACS Chemical Biology, 8, 82–95. https://doi.org/10.1021/cb300648v
Pongrakhananon, V., & Rojanasakul, Y. (2012). Anticancer properties of
curcumin. Advanced Cancer Therapeutics, 345–368. https://doi.org/10.
5772/23594
Prieto-Vila, M., Takahashi, R. U., Usuba, W., Kohama, I., & Ochiya, T.
(2017). Drug resistance driven by cancer stem cells and their niche.
International Journal of Molecular Sciences, 18, 2574. https://doi.org/
10.3390/ijms18122574
21
Punfa, W., Yodkeeree, S., Pitchakarn, P., Ampasavate, C., & Limtrakul, P.
(2012). Enhancement of cellular uptake and cytotoxicity of curcumin-
loaded PLGA nanoparticles by conjugation with anti-P-glycoprotein in
drug resistance cancer cells. Acta Pharmacologica Sinica, 33, 823–831.
https://doi.org/10.1038/aps.2012.34
Rahmani, A. H., Al Zohairy, M. A., Aly, S. M., & Khan, M. A. (2014). Cur-
cumin: A potential candidate in prevention of cancer via modulation of
molecular pathways. BioMed Research International, 2014, 761608.
https://doi.org/10.1155/2014/761608
Rai, M., Pandit, R., Gaikwad, S., Yadav, A., & Gade, A. (2015). Potential
applications of curcumin and curcumin nanoparticles: From traditional
therapeutics to modern nanomedicine. Nanotechnology Reviews, 4.
https://doi.org/10.1515/ntrev-2015-0001
Ramachandran, C., Rodriguez, S., Ramachandran, R., Nair, P. K. R.,
Fonseca, H., Khatib, Z., … Melnick, S. J. (2005). Expression profiles of
apoptotic genes induced by curcumin in human breast cancer and
mammary epithelial cell lines. Anticancer Research, 25, 3293–3302.
Razaghi, A., Heimann, K., Schaeffer, P. M., & Gibson, S. B. (2018). Negative
regulators of cell death pathways in cancer: Perspective on biomarkers
and targeted therapies. Apoptosis, 23, 93–112. https://doi.org/10.
1007/s10495-018-1440-4
Reuter, S., Gupta, S. C., Park, B., Goel, A., & Aggarwal, B. B. (2011). Epige-
netic changes induced by curcumin and other natural compounds.
Genes & Nutrition, 6, 93–108. https://doi.org/10.1007/s12263-011-
0222-1
Revalde, J. L., Li, Y., Hawkins, B. C., Rosengren, R. J., & Paxton, J. W.
(2015). Heterocyclic cyclohexanone monocarbonyl analogs of cur-
cumin can inhibit the activity of ATP-binding cassette transporters in
cancer multidrug resistance. Biochemical Pharmacology, 93, 305–317.
https://doi.org/10.1016/j.bcp.2014.12.012
Rives, V., Del Arco, M., & Martín, C. (2013). Layered double hydroxides as
drug carriers and for controlled release of non-steroidal
antiinflammatory drugs (NSAIDs): A review. Journal of Controlled
Release, 169, 28–39. https://doi.org/10.1016/j.jconrel.2013.03.034
Rivlin, N., Brosh, R., Oren, M., & Rotter, V. (2011). Mutations in the p53
tumor suppressor gene: Important milestones at the various steps of
tumorigenesis. Genes and Cancer, 2, 466–474. https://doi.org/10.
1177/1947601911408889
Robey, R. W., Polgar, O., Deeken, J., To, K. W., & Bates, S. E. (2007).
ABCG2: determining its relevance in clinical drug resistance. Cancer
and Metastasis Reviews, 26, 39–57. https://doi.org/10.1007/s10555-
007-9042-6
Rocha, C., Silva, M., Quinet, A., Cabral-Neto, J., & Menck, C. (2018). DNA
repair pathways and cisplatin resistance: An intimate relationship.
Clinics, 73, 1–10. https://doi.org/10.6061/clinics/2018/e478s
Rowe, D. L., Ozbay, T., O'Regan, R. M., & Nahta, R. (2009). Modulation of
the BRCA1 protein and induction of apoptosis in triple negative breast
cancer cell lines by the polyphenolic compound curcumin. Breast Can-
cer: Basic and Clinical Research, 3, 61–75.
Roy, M., & Mukherjee, S. (2014). Reversal of resistance towards cisplatin by
curcumin in cervical cancer cells. Asian Pacific Journal of Cancer Prevention,
15, 1403–1410. https://doi.org/10.7314/apjcp.2014.15.3.1403
Roy, S., Yu, Y., Padhye, S. B., Sarkar, F. H., & Majumdar, A. P. N. (2013).
Difluorinated-curcumin (CDF) restores PTEN expression in colon can-
cer cells by down-regulating miR-21. PLoS ONE, 8, 5–10. https://doi.
org/10.1371/journal.pone.0068543
Saha, S., Adhikary, A., Bhattacharyya, P., Das, T., & Sa, G. (2012). Death by
design: Where curcumin sensitizes drug-resistant tumours. Anticancer
Research, 32, 2567–2584.
Salehan, M. R., & Morse, H. R. (2013). DNA damage repair and tolerance:
A role in chemotherapeutic drug resistance. British Journal of Biomedi-
cal Science, 70, 31–40. https://doi.org/10.1080/09674845.2013.
11669927
Sanaei, M., & Kavoosi, F. (2018). Effect of curcumin and trichostatin a on
the expression of DNA methyltransfrase 1 in hepatocellular carcinoma
22
cell line hepa 1-6. The Iranian Journal of Pediatric Hematology & Oncol-
ogy, 8, 193–201.
Sarkadi, B., Homolya, L., Szakács, G., & Váradi, A. (2006). Human multidrug
resistance ABCB and ABCG transporters: Participation in a
chemoimmunity defense system. Physiological Reviews, 86,
1179–1236. https://doi.org/10.1152/physrev.00037.2005
Selvendiran, K., Tong, L., Vishwanath, S., Bratasz, A., Trigg, N. J.,
Kutala, V. K., … Kuppusamy, P. (2007). EF24 induces G2/M arrest and
apoptosis in cisplatin-resistant human ovarian cancer cells by increas-
ing PTEN expression. The Journal of Biological Chemistry, 282,
28609–28618. https://doi.org/10.1074/jbc.M703796200
Shakibaei, M., Buhrmann, C., Kraehe, P., Shayan, P., Lueders, C., & Goel, A.
(2014). Curcumin chemosensitizes 5-fluorouracil resistant MMR-
deficient human colon cancer cells in high density cultures. PLoS ONE,
9, 1–12. https://doi.org/10.1371/journal.pone.0085397
Shang, H. S., Chang, C. H., Chou, Y. R., Yeh, M. Y., Au, M. K., Lu, H. F., …
Chung, J. G. (2016). Curcumin causes DNA damage and affects
associated protein expression in HeLa human cervical cancer cells.
Oncology Reports, 36, 2207–2215. https://doi.org/10.3892/or.
2016.5002
Shanmugam, M. K., Rane, G., Kanchi, M. M., Arfuso, F., Chinnathambi, A.,
Zayed, M. E., … Sethi, G. (2015). The multifaceted role of curcumin in
cancer prevention and treatment. Molecules, 20, 2728–2769. https://
doi.org/10.3390/molecules20022728
Sharma, R. A., Euden, S. A., Platton, S. L., Cooke, D. N., Shafayat, A.,
Hewitt, H. R., … Steward, W. P. (2004). Phase I clinical trial of oral cur-
cumin: Biomarkers of systemic activity and compliance. Clinical Cancer
Research, 10, 6847–6854. https://doi.org/10.1158/1078-0432.CCR-
04-0744
Shimizu, M., Gruz, P., Kamiya, H., Kim, S. R., Pisani, F. M., Masutani, C., …
Nohmi, T. (2003). Erroneous incorporation of oxidized DNA precursors
by Y-family DNA polymerases. EMBO Reports, 4, 269–273. https://
doi.org/10.1038/sj.embor.embor765
Shishodia, S., Amin, H. M., Lai, R., & Aggarwal, B. B. (2005). Curcumin
(diferuloylmethane) inhibits constitutive NF-κB activation, induces
G1/S arrest, suppresses proliferation, and induces apoptosis in mantle
cell lymphoma. Biochemical Pharmacology, 70, 700–713. https://doi.
org/10.1016/j.bcp.2005.04.043
Siddik, Z. H. (2003). Cisplatin: Mode of cytotoxic action and molecular
basis of resistance. Oncogene, 22, 7265–7279. https://doi.org/10.
1038/sj.onc.1206933
Simental-Mendía, L. E., & Sahebkar, A. (2016). Modulation of microRNAs
by curcumin in pancreatic cancer. Clinical Nutrition, 35, 1585. https://
doi.org/10.1016/j.clnu.2016.09.001
Soria, J. C., Smit, E., Khayat, D., Besse, B., Yang, X., Hsu, C. P., …
Blackhall, F. (2010). Phase 1b study of dulanermin (recombinant
human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and
bevacizumab in patients with advanced non-squamous non-small-cell
lung cancer. Journal of Clinical Oncology, 28, 1527–1533. https://doi.
org/10.1200/JCO.2009.25.4847
Spiros, A. V. (2017). Aberrant control of NF-κB in cancer permits transcrip-
tional and phenotypic plasticity, to curtail dependence on host tissue:
Molecular mode. Cancer Biology & Medicine, 14, 254. https://doi.org/
10.20892/j.issn.2095-3941.2017.0029
Sreenivasan, S., Thirumalai, K., Danda, R., & Krishnakumar, S. (2012). Effect
of curcumin on miRNA expression in human Y79 retinoblastoma cells.
Current Eye Research, 37, 421–428. https://doi.org/10.3109/
02713683.2011.647224
Srivastava, A. K., Han, C., Zhao, R., Cui, T., Dai, Y., Mao, C., … Wang, Q.-E.
(2015). Enhanced expression of DNA polymerase eta contributes to
cisplatin resistance of ovarian cancer stem cells. Proceedings of the
National Academy of Sciences, 112, 4411–4416. https://doi.org/10.
1073/pnas.1421365112
Stover, E. H., Konstantinopoulos, P. A., Matulonis, U. A., & Swisher, E. M.
(2016). Biomarkers of response and resistance to DNA repair targeted
KEYVANI-GHAMSARI ET AL.
therapies. Clinical Cancer Research, 22, 5651–5660. https://doi.org/10.
1158/1078-0432.CCR-16-0247
Subramaniam, D., Ponnurangam, S., Ramamoorthy, P., Standing, D.,
Battafarano, R. J., Anant, S., & Sharma, P. (2012). Curcumin induces
cell death in esophageal cancer cells through modulating notch signal-
ing. PLoS ONE, 7, e30590. https://doi.org/10.1371/journal.pone.
0030590
Syng-Ai, C., Kumari, A. L., & Khar, A. (2004). Effect of curcumin on normal
and tumor cells: Role of glutathione and bcl-2. Molecular Cancer Thera-
peutics, 3, 1101–1108.
Talalay, P. (2000). Chemoprotection against cancer by induction of phase
2 enzymes. BioFactors, 12, 5–11. https://doi.org/10.1002/biof.
5520120102
Talib, W. H., Al-hadid, S. A., Wild Ali, M. B., Al-Yasari, I. H., & Abd
Ali, M. R. (2018). Role of curcumin in regulating p53 in breast
cancer: An overview of the mechanism of action. Breast Cancer: Tar-
gets and Therapy, 10, 207–217. https://doi.org/10.2147/BCTT.
S167812
Tan, B. L., & Norhaizan, M. E. (2019). Curcumin combination chemother-
apy: The implication and efficacy in cancer. Molecules, 24, 1–21.
https://doi.org/10.3390/molecules24142527
Tomeh, M. A., Hadianamrei, R., & Zhao, X. (2019). A review of curcumin
and its derivatives as anticancer agents. International Journal of Molecu-
lar Sciences, 20, 1033. https://doi.org/10.3390/ijms20051033
Tripathi, A., & Misra, K. (2016). Designing and development of novel cur-
cumin analogues/congeners as inhibitors of breast Cancer stem cells
growth. Chemical Engineering Transactions, 49, 79–84. https://doi.org/
10.3303/CET1649014
Tsai, L. L., Yu, C. C., Lo, J. F., Sung, W. W., Lee, H., Chen, S. L., &
Chou, M. Y. (2012). Enhanced cisplatin resistance in oral-cancer stem-
like cells is correlated with upregulation of excision-repair cross-
complementation group 1. The Journal of Dental Sciences, 7, 111–117.
https://doi.org/10.1016/j.jds.2012.03.006
Um, Y., Cho, S., Woo, H. B., Kim, Y. K., Kim, H., Ham, J., … Lee, S. (2008).
Synthesis of curcumin mimics with multidrug resistance reversal activi-
ties. Bioorganic & Medicinal Chemistry, 16, 3608–3615. https://doi.org/
10.1016/j.bmc.2008.02.012
Vallianou, N. G., Evangelopoulos, A., Schizas, N., & Kazazis, C. (2015).
Potential anticancer properties and mechanisms of action of curcumin.
Anticancer Research, 35, 645–651.
Vinod, B. S., Antony, J., Nair, H. H., Puliyappadamba, V. T., Saikia, M., Shyam
Narayanan, S., … John Anto, R. (2013). Mechanistic evaluation of the sig-
naling events regulating curcumin-mediated chemosensitization of breast
cancer cells to 5-fluorouracil. Cell Death & Disease, 4, e505–e513.
https://doi.org/10.1038/cddis.2013.26
Vosooghi, M., Firoozpour, L., Rodaki, A., Pordeli, M., Safavi, M.,
Ardestani, S. K., … Foroumadi, A. (2014). Design, synthesis, docking
study and cytotoxic activity evaluation of some novel letrozole ana-
logs. DARU. Journal of Pharmaceutical Sciences, 22, 1–7. https://doi.
org/10.1186/s40199-014-0083-4
Wang, B., Liu, X., Teng, Y., Yu, T., Chen, J., Hu, Y., … Shen, Y. (2017).
Improving anti-melanoma effect of curcumin by biodegradable
nanoparticles. Oncotarget, 8, 108624–108642. https://doi.org/10.
18632/oncotarget.20585
Wang, P., Yang, H. L., Yang, Y. J., Wang, L., & Lee, S. C. (2015). Overcome
Cancer Cell Drug Resistance Using Natural Products. Evidence-Based
Complementary and Alternative Medicine, 2015, 14. https://doi.org/10.
1155/2015/767136
Wang, Z., Sun, H., Provaznik, J., Hackert, T., & Zöller, M. (2019). Pancreatic
cancer-initiating cell exosome message transfer into noncancer-
initiating cells: The importance of CD44v6 in reprogramming. Journal
of Experimental & Clinical Cancer Research, 38, 1–20. https://doi.org/
10.1186/s13046-019-1129-8
Wang, Z., Sun, W., Huang, C. K., Wang, L., Ia, M. M., Cui, X., … Wang, Z. S.
(2015). Inhibitory effects of curcumin on activity of cytochrome P450
KEYVANI-GHAMSARI ET AL.
2C9 enzyme in human and 2C11 in rat liver microsomes. Drug Devel-
opment and Industrial Pharmacy, 41, 613–616. https://doi.org/10.
3109/03639045.2014.886697
Wei, Y., Pu, X., & Zhao, L. (2017). Preclinical studies for the combina-
tion of paclitaxel and curcumin in cancer therapy (review). Oncol-
ogy Reports, 37, 3159–3166. https://doi.org/10.3892/or.2017.
5593
Wilken, R., Veena, M. S., Wang, M. B., & Srivatsan, E. S. (2011). Curcumin:
A review of anti-cancer properties and therapeutic activity in head and
neck squamous cell carcinoma. Molecular Cancer, 10, 12. https://doi.
org/10.1186/1476-4598-10-12
Wilkens, S. (2015). Structure and mechanism of ABC transporters.
F1000Prime Reports, 7, 14. https://doi.org/10.12703/P7-14
Wong, R. S. Y. (2011). Apoptosis in cancer: From pathogenesis to treat-
ment. Journal of Experimental & Clinical Cancer Research, 30, 87.
https://doi.org/10.1186/1756-9966-30-87
Xia, L., Tan, S., Zhou, Y., Lin, J., Wang, H., Oyang, L., … Liao, Q. (2018). Role
of the NFκB-signaling pathway in cancer. Oncotargets and Therapy, 11,
2063–2073. https://doi.org/10.2147/OTT.S161109
Yan, G., Graham, K., & Lanza-Jacoby, S. (2013). Curcumin enhances the
anticancer effects of trichostatin a in breast cancer cells. Molecular
Carcinogenesis, 52, 404–411. https://doi.org/10.1002/mc.21875
Yang, J., Cao, Y., Sun, J., & Zhang, Y. (2010). Curcumin reduces the expres-
sion of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells.
Medical Oncology, 27, 1114–1118. https://doi.org/10.1007/s12032-
009-9344-3
Yallapu, M. M., Jaggi, M., & Chauhan, S. C. (2013). Curcumin nanomedicine: A
road to cancer therapeutics. Current Pharmaceutical Design, 19,
1994–2010. https://doi.org/10.2174/1381612811319110004
You, Y., Bi, F. F., Jiang, Y., Xu, Y. T., An, Y. Y., Li, D., & Yang, Q. (2019).
BRCA1 affects the resistance and stemness of SKOV3-derived ovarian
cancer stem cells by regulating autophagy. Cancer Medicine, 8,
656–668. https://doi.org/10.1002/cam4.1975
Zahreddine, H., & Borden, K. L. B. (2013). Mechanisms and insights into
drug resistance in cancer. Frontiers in Pharmacology, 4, 1–8. https://
doi.org/10.3389/fphar.2013.00028
Zaman, M. S., Chauhan, N., Yallapu, M. M., Gara, R. K., Maher, D. M.,
Kumari, S., … Chauhan, S. C. (2016). Curcumin nanoformulation for
cervical cancer treatment. Scientific Reports, 6, 1–14. https://doi.org/
10.1038/srep20051
Zhang, C., Xu, Y., Wang, H., Li, G., Yan, H., Fei, Z., … Li, W. (2018). Cur-
cumin reverses irinotecan resistance in colon cancer cell by regulation
of epithelial-mesenchymal transition. Anti-Cancer Drugs, 29, 334–340.
https://doi.org/10.1097/CAD.0000000000000599
Zhang, W., Shi, H., Chen, C., Ren, K., Xu, Y., Liu, X., & He, L. (2018). Cur-
cumin enhances cisplatin sensitivity of human NSCLC cell lines
23
through influencing Cu-Sp1-CTR1 regulatory loop. Phytomedicine, 48,
51–61. https://doi.org/10.1016/j.phymed.2018.04.058
Zhang, X., Chen, Q., Wang, Y., Peng, W., & Cai, H. (2014). Effects of cur-
cumin on ion channels and transporters. Frontiers in Pharmacology, 5,
1–6. https://doi.org/10.3389/fphys.2014.00094
Zhang, Y., & Wang, J. (2017). MicroRNAs are important regulators of drug
resistance in colorectal cancer. Biological Chemistry, 398, 929–938.
https://doi.org/10.1515/hsz-2016-0308
Zhang, Z., Han, H., Rong, Y., Zhu, K., Zhu, Z., Tang, Z., … Tao, J. (2018).
Hypoxia potentiates gemcitabine-induced stemness in pancreatic
cancer cells through AKT/Notch1 signaling. Journal of Experimental &
Clinical Cancer Research, 37, 1–13. https://doi.org/10.1186/
s13046-018-0972-3
Zhao, G., Han, X., Zheng, S., Li, Z., Sha, Y., Ni, J., … Song, Z. (2016). Curcumin
induces autophagy, inhibits proliferation and invasion by downregulating
AKT/mTOR signaling pathway in human melanoma cells. Oncology
Reports, 35, 1065–1074. https://doi.org/10.3892/or.2015.4413
Zhao, Q., Guan, J., Qin, Y., Ren, P., Zhang, Z., Lv, J., … Mao, W. (2018). Cur-
cumin sensitizes lymphoma cells to DNA damage agents through regu-
lating Rad51-dependent homologous recombination. Biomedicine &
Pharmacotherapy, 97, 115–119. https://doi.org/10.1016/j.biopha.
2017.09.078
Zheng, J., Wu, C., Lin, Z., Guo, Y., Shi, L., Dong, P., … Yu, F. (2014). Cur-
cumin up-regulates phosphatase and tensin homologue deleted on
chromosome 10 through microRNA-mediated control of DNA
methylation—A novel mechanism suppressing liver fibrosis. The FEBS
Journal, 281, 88–103. https://doi.org/10.1111/febs.12574
Zhou, W., Chen, Y. W., Liu, X., Chu, P., Loria, S., Wang, Y., … Chou, K. M.
(2013). Expression of DNA translesion synthesis polymerase η in head
and neck squamous cell cancer predicts resistance to gemcitabine and
cisplatin-based chemotherapy. PLoS ONE, 8, 1–10. https://doi.org/10.
1371/journal.pone.0083978
Zou, J., Zhu, L., Jiang, X., Wang, Y., Wang, Y., Wang, X., & Chen, B. (2018).
Curcumin increases breast cancer cell sensitivity to cisplatin by
decreasing FEN1 expression. Oncotarget, 9, 11268–11278. https://
doi.org/10.18632/oncotarget.24109
How to cite this article: Keyvani-Ghamsari S, Khorsandi K,
Gul A. Curcumin effect on cancer cells' multidrug resistance:
An update. Phytotherapy Research. 2020;1–23. https://doi.
org/10.1002/ptr.6703