Biomedicine & Pharmacotherapy 117 (2019) 109086

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

The mechanism of anticancer action and potential clinical use of kaempferol T

in the treatment of breast cancer
⁎
Xueni Wanga, Yuting Yanga,b, Yating Anc, Gang Fanga,d,
a
Guangxi Zhuang Yao Medicine Center of Engineering and Technology, Guangxi University of Chinese Medicine, 13 Wuhe Road, Qingxiu District, Nanning, 530200, China
b
Faculty of pharmacy, Guangxi University of Chinese Medicine, 13 Wuhe Road, Qingxiu District, Nanning, 530200, China
c
Department of pharmacy, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, 354 North road, Hongqiao District, Tianjin, 300120, China
d
Laboratory of Zhuang Medicine Prescriptions Basis and application Research, Guangxi University of Chinese medicine, 179 Mingxiudong Road, Xixiangtang District,
Nanning, 530001, China

A R T I C LE I N FO A B S T R A C T

Keywords: In the last century, natural compounds have achieved remarkable achievements in the treatment of tumors
Kaempferol through chemotherapy. This inspired scientists to continuously explore anticancer agents from natural com-
Breast cancer pounds. Kaempferol is an ordinary natural compound, the most common flavonoid, which is widely existed in
Mechanism vegetables and fruits. It has been reported to have various anticancer activities, including breast cancer, prostate
cancer, bladder cancer, cervical cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, leukemia, etc.
Meanwhile, we found that there were more reports on breast cancer among these cancers although there are
limited clinical studies that have addressed the benefits of kaempferol as an anti-cancer agent for breast cancer
treatment. Then we realize that although kaempferol has been reported to have anti-breast cancer effect many
times, it is still far from becoming a real anti-breast cancer agent. Therefore, in this review, we talk about the
options for improving the anti-breast cancer effect of kaempferol, including various techniques and methods to
improve the bioavailability of kaempferol, the idea of combining other compounds to produce synergistic effects,
and the possibility of developing kaempferol into a targeted drug delivery system.

1. Background Anti-estrogens are very effective on reducing the risk of breast

Breast cancer is one of the deadliest diseases for women in western
countries [1]. The global incidence of breast cancer has been rising
since the late 1970s. In the United States, a woman is 12.4 percent more
likely to be diagnosed with breast cancer in her lifetime. In other words,
each eight women in the United States have one breast cancer in their
lifetime [2]. China is not a country with high incidence of breast cancer,
but it is not optimistic. Although Asian women have a lower incidence
of breast cancer than white women, the incidence of breast cancer in
China has been on the rise [1]. Current treatments for breast cancer
include surgery, medicines, and radiation therapy [3]. And the medi-
cation of breast cancer mainly includes anti-estrogen drugs [4], ar-
omatase inhibitors, [4], Anti-angiogenesis drugs [5], Monoclonal anti-
body drugs [6], Anthracyclines [7], and other drugs.
cancer, but long-term use can cause multiple side effects [8–10]. Ar-
omatase inhibitors also have been shown to be effective in treating
women with early stage breast cancer [11]. However, some studies
suggest that aromatase inhibitors may have potential cardiotoxicity
[12]. Anti-angiogenesis drugs can inhibit the development and growth
of breast cancer and lead to its ischemic death [13]. Mounting studies
showed that the monoclonal antibody drugs had a significant antic-
ancer effect and could improve the survival ability of patients. How-
ever, these agents were only applicable to patients with HER2-positive
breast cancer, and most of them were expensive and could cause serious
side effects after administration [6,14]. Anthracyclines are better for
breast cancer than many other chemotherapy drugs. But it also has side
effects, such as damage to the heart and nail pigmentation [15,16].
Clinical data have shown that many natural molecules isolated from

Abbreviations: Bax, BCL2-Associated X; Bcl-2, B-cell lymphoma-2; CDK1, cyclin-dependent kinases; EMT, Epithelial-Mesenchymal Transition; ERR, estrogen-related
receptor; ER, estrogen receptor; E2, estradiol; FAS, fatty acid synthase; G1, first gap; G2, second gap; HER2, human epidermal growth factor receptor-2; irs-1, receptor
matrix 1; LNCaP, prostate cancer cell line; MMPs, matrix metalloproteninases; NQO1, quinone oxidoreductase 1; NRF2, nuclear fac-tor erythroid 2-related factor 2;
PARP, poly ADP-ribose polymerase; PR, progesterone receptor; SN, Solanum nigrum Linn; TNBC, triple negative breast cancers
⁎
Corresponding author at: Guangxi Zhuang Yao Medicine Center of Engineering and Technology, Guangxi University of Chinese Medicine, 13 Wuhe Road, Qingxiu
District, Nanning, 530200, China.
E-mail addresses: wangxueni@yeah.net (X. Wang), yangyuting2018@sina.com (Y. Yang), sherry_ayt@163.com (Y. An), fglzyznn@gxtcmu.edu.cn (G. Fang).

https://doi.org/10.1016/j.biopha.2019.109086
Received 4 May 2019; Received in revised form 2 June 2019; Accepted 4 June 2019
0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
X. Wang, et al.
herbs have significant anti-breast cancer efficacy, such as Paclitaxel,
[17] vincristine [18], cantharidin sodium injection [19], Magnolol
[20–22].
These natural compounds have achieved remarkable therapeutic
effects in the treatment of cancer by chemotherapy. In addition, sci-
entists are constantly developing new ways to treat cancer. Among
them, the rapid development of immunotherapy methods is particularly
eye-catching. Immunotherapy has continued to bring new evangelism
to patients in recent years. As a researcher developing natural medicine,
when our eyes leave the microscope, we may suddenly feel unseeing.
Do our work still meaningful, can our work save more lives, or what
changes can our work bring to patients?
Flavonoids, the most abundant polyphenols in the human diet, are
found mainly in vegetables, fruits and botanical drinks and are the main
ingredient in many herbal products. Large amounts of flavonoids can
reduce the risk of cancer, according to epidemiological and animal
studies [23,24]. Kaempferol is one the most common dietary flavonols.
Mounting studies have confirmed that kaempferol has a certain ther-
apeutic effect as a chemotherapy drug for breast cancer [23,25].
Herein, we summarized the mechanism of kaempferol in the treat-
ment of breast cancer. We found that kaempferol mainly produced anti
breast cancer effects in three following ways:(1) inhibiting the growth
of breast cancer cells; (2) inducing the apoptosis of breast cancer cells;
(3) inhibiting migration and invasion of breast cancer cells. However,
these are common ways of many natural compounds against cancer,
and they cannot kill cancer cells rapid and specifically. Moreover,
kaempferol's bioavailability was reported to very low, as low as 2%
[26,27]. All These findings illuminate that kaempferol has a prospect in
treatment of breast cancer while there are still many problems to be
resolved.
2. Kaempferol inhibits the growth of breast cancer cells
Kaempferol arrests cell cycle at G2/M stage through downregulation
of CDK1 in human breast cancer MDA-MB-453 cells [5]. Similar find-
ings were obtained by Zhu’s team in triple negative breast cancer cells.
Their study showed that after treatment with kaempferol, the number
of cells in first gap G1 phase decreased significantly from 85.48% to
51.35%, and the number of cells in G2 phase increased significantly
from 9.27% to 37.5% [28]. These findings indicate that kaempferol can
inhibit cell growth by destroying the cell cycle. (Fig.1A)
Since stability of glucose concentration is critical to maintaining
cancer cells, inhibiting glutamate-mediated glucose transport is con-
sidered to be a potential strategy for cancer treatment [29,30]. Study by
Claudia Azevedo and her team showed that kaempferol can effectively
Fig. 1. Overview of the mechanism of kaempferol inhibiting the proliferation of breast cancer cells.
2
Biomedicine & Pharmacotherapy 117 (2019) 109086
inhibit the glucose uptake of MCF-7 breast cancer cells, leading to a
significant decline in cell viability and proliferation ability, thus in-
hibiting the growth of breast cancer cells. Furthermore, they found that
kaempferol could also inhibit the absorption of lactic acid in MCF-7
breast cancer cells, leading to cancer cell death [31]. (Fig.1B)
The anticancer action of Kaempferol role also can be mediated by
ER. Hung et al. reported that kaempferol could induce the degradation
of ERα and prevented the estradiol-induced cell proliferation at
17.5–70 μM in MCF-7 cells [32]. Kim et al. found that kaempferol could
markedly repress 17β-estradiol or triclosan-induced MCF-7 breast
cancer cells growth via nongenomic ER signaling pathway associated
with IGF-1R. It is noteworthy that they have obtain consistent result in
an in vivo xenografted mouse model [33]. (Fig.1C)
3. Kaempferol induces apoptosis of breast cancer cells
PARP is the cutting substrate of caspase, the core of cell apoptosis. It
plays an important role in DNA damage repair and cell apoptosis. PARP
shear is considered as an important indicator of apoptosis. The apop-
totic-preventing protein Bcl2 and the pro-apoptotic protein Bax were
also involved in the process. The study of Yi et al. showed that
kaempferol could effectively induce the cleavage of PARP expression in
MCF-7 cells, moreover, they detected that the outcome was accom-
panied by downregulating Bcl2 protein expression and promoting Bax
protein expression [34]. (Fig.2A) Brusselmans and his team provided a
new mechanism that Kaempferol and four other flavonoids induced
apoptosis of MDA-MB231 cells, which was strongly associated with the
properties of inhibiting fatty acid synthesis [35]. (Fig.2, B) However,
other scientists have different findings. Liao et al. found that kaemp-
ferol could also induce apoptosis in MCF-7 cells, whereby the reactive
oxygen species were the cause of induction of apoptosis [36]. (Fig.2C)
4. Kaempferol inhibit the migration and invasion of breast cancer
cells
Epithelial-Mesenchymal Transition (EMT) is considered to play a
major role in the development of breast cancer. Studies have found that
EMT of breast cancer cells will resist chemotherapy, so that the effi-
ciency of chemotherapy will be reduced or even failed [37]. studies by
Lee et al. showed that Kaempferol can effectively inhibit the metastatic
behavior of breast cancer caused by endogenous estrogen and exo-
genous heterologous compounds evidenced by Kaempferol could ef-
fectively inhibit the expression of E2 or triclosan-induced EMT and
metastatic proteins [38]. (Fig. 3A)
As a marker of poor prognosis of breast cancer, matrix
X. Wang, et al.
Fig. 2. Overview of the mechanism of apoptosis induced by kaempferol in breast cancer cells.
metalloproteinase has been used as a target for the treatment of breast
cancer [39]. Some studies suggest that MMP1, MMP3 and MMP9 gene
polymorphisms have synergistic effect on breast cancer. MMPs inter-
action has shown a strong correlation with clinical risk factors (such as
lymph node metastasis) and may affect the 5-year survival rate [40].
MMP-3 is an enzyme related to tumor invasion and metastasis, Chu
et al. confirmed that microRNAs (miR-519d) can inhibit the occurrence
and metastasis of breast cancer [41]. Mounting studies have shown that
the most aggressive breast cancers express highest level of MMP-3, and
suppress MMP-3 expression could reduce invasion and migration of
various human malignant cell lines [42]. In the study of Phromnoi
et al., they found kaempferol could dramatically inhibit the invasion
ability of MDA-MB-231 cells, with IC50 values of 30 μmol/L. Simulta-
neously, they also found kaempferol could reduce MMP-3 activity with
IC50 values of 45 μmol/L. It is noteworthy that kaempferol could
markedly inhibit the hydrolytic activity of MMP-3 casein and then in-
hibit the invasion ability of breast cancer cells [43]. Li et al. also found
that Kaempferol inhibited the invasion of breast cancer cells was related
to matrix metalloproteinases. Their study showed that kaempferol in-
hibited cancer cells invasion through blocking the PKCδ/ MAPK/AP-1
cascade and subsequent MMP-9 expression and its activity [44].
(Fig. 3B)
Triple negative breast cancer refers to the type of breast cancer that
is negative for estrogen receptor (ER), progesterone receptor (PR) and
human epidermal growth factor receptor 2 (her-2), accounting for
Fig. 3. Mechanism of kaempferol inhibiting migration and invasion of breast cancer cells.
3
Biomedicine & Pharmacotherapy 117 (2019) 109086
15%–25% of all pathological types of breast cancer, mostly occurring in
premenopausal women [45,46]. Systemic therapy for patients with
nonmetastatic TNBC is chemotherapy alone. Local therapy for patients
with nonmetastatic TNBC Including surgical resection and, if necessary,
radiotherapy [47]. Scientists found that low doses of kaempferol
(20 μmol/L) reduced RhoA and Rac1 activation in TNBC cells and then
inhibited its migration and invasion via blocking RhoA and Rac1 sig-
naling pathways [48]. In addition, some other scientists reported that
kaempferol was a strong NRF2 inducer, it can regulate the expression of
NRF2 and its NQO1 enzyme in MCF-7cells, thus inhibiting the trans-
formation of oncogenes [49]. (Fig. 3C)
5. Discussion
Although scientists around the world have been developing new
treatments, the latest global cancer data show that breast cancer has the
highest morbidity and mortality among women in the world [50]. Ac-
cording to the latest cancer statistics, the highest incidence of breast
cancer is in Australia and New Zealand (94.2 Age-standardized (W) rate
per 100,000), followed by Western Europe (92.6 Age-standardized (W)
rate per 100,000) and Northern Europe (90.1 Age-standardized (W)
rate per 100,000), while the incidence of breast cancer in East Asia is
relatively low (39.2 Age-standardized(W)rate per 100,000) [50]. Stu-
dies have shown that the low incidence of breast cancer in East Asia,
especially in China, is related to their daily consumption of foods
X. Wang, et al.
containing large amounts of flavonoids [51]. In addition, a number of
studies have confirmed the role of flavonoids in the prevention and
treatment of breast cancer [52,53]. Actually, the anti-breast cancer
effect of natural compounds has always been one of the areas of concern
to scientists. In this review, we reviewed several approaches of
kaempferol in the treatment of breast cancer, and concluded that
kaempferol has certain curative effect on breast cancer, which provides
certain basis for the follow-up study of breast cancer.
By analyzing the collected literature, we found that kaempferol
produced anti-breast cancer effects in vivo and in vitro mainly by in-
hibiting cell proliferation, preventing cell migration and inducing
apoptosis. However, the oral bioavailability of kaempferol is very low.
If it is to be developed into a good oral preparation, it is necessary to
use other auxiliary means to improve its bioavailability. Qian et al.
greatly improved the oral bioavailability of kaempferol by preparing
kaempferol into a nanosuspension, by using pressure homogenization
(HPH) techniques. [54] Xu et al. prepared kaempferol and poly-
saccharide arabinogalactan and disodium glycyrrhizinate into com-
plexes, by mechanochemical technique, which also increased the so-
lubility and bioavailability of kaempferol [55]. According to a recent
study, scientists prepared kaempferol and Poloxamer 407 into a solid
dispersion, greatly improving the water solubility and oral bioavail-
ability of kaempferol [56]. These studies indicate that scientists have a
variety of ways to improve the oral bioavailability of kaempferol.
Several types of malignant tumors, including breast carcinoma,
whose cells proliferate intensively, represent very dynamic structures
that create numerous mutations resulting in new tumor cell lines with
different genotypes and phenotypes within the tumor mass. In such
malignances, a highly variable sensitivity to therapeutics can be ob-
served and some of cell lines develop resistance to the treatment [57].
The biological effects of combining various phytochemicals to target a
range of signaling pathways within the cancer cells should be superior
compared to single compound targeting only one signaling pathway
[57,58]. Kaempferol administered in the combination with other fruit
peel polyphenols such as myricetin, quercetin, rutin, catechin, epica-
techin, anthocyanidins, or resveratrol demonstrated excellent antic-
ancer activity in robust preclinical study using the model of chemically-
induced rat mammary carcinogenesis and MCF-7 and MDA-MB-231
breast cancer cell lines [59]. Ackland et al.’s research also have shown
that kaempferol combined with quercetin has a stronger inhibitory ef-
fect on the proliferation of PMC42 breast cancer cells than each of them
alone [60]. Other scientists have also found synergistic effects of
kaempferol in combination with other compounds in ovarian cancer
cells. Luo et al. 's study reveals that kaempferol enhances the anti-
ovarian cancer effect of cisplatin by promoting apoptosis [61]. In ad-
dition, Zhang et al. found that kaempferol combined with several other
flavonoids could produce a stronger inhibitory effect on the expression
of ABCG2, the breast cancer resistance protein [62]. These studies
suggest that kaempferol can be combined with other compounds to
enhance its anticancer effect and drug resistance. Scientists can do
deeper and broader research in this area. In the following, scientists can
do more research in this area to improve the anti-breast cancer effect of
kaempferol.
In addition to improving bioavailability and anticancer effects,
kaempferol, like other anticancer compounds, faces the problem of how
it can be accurately transported to breast cancer tissues and cells, then
produce precise anticancer effects. Obviously, if kaempferol can be
developed into a targeted drug delivery system, then it would exert the
anticancer effects in designated sites or tissues. It is worth noting that
some progress has been made in the study of targeted agents for breast
cancer. Beh et al. constructed tamoxifen and nanostructured lipid car-
riers into a drug delivery system targeting erythropoietin receptor, so
that tamoxifen can identify breast cancer cells expressing ery-
thropoietin receptor and produce cytotoxicity at designated sites [63].
Another group of scientists established a nanovehicle-based Multistage
Drug-Delivery System targeting HER2 to treat breast cancer with HRE2
4
Biomedicine & Pharmacotherapy 117 (2019) 109086
overexpression, they found that the system had a stronger inhibitory
effect on tumor cells in vivo and in vitro, and it also reduced damage to
normal tissue [64]. In addition, Wang et al. established a mesoporous
targeted drug delivery system for the treatment of triple negative breast
cancer. The system is mediated by intercellular adhesion molecule-1
antibody and can load a large amount of doxorubicin. It takes more
doxorubicin into and accumulate in triple-negative breast cancer cells,
resulting in stronger therapeutic effects [65]. Inspired by the above
studies, kaempferol can also be designed as a targeted drug delivery
system to achieve stronger and more accurate anticancer effects.
However, more research is needed on which targeted drug delivery
system kaempferol could be developed into.
6. Conclusions
In general, a large number of preclinical studies have confirmed the
role of kaempferol in the prevention and treatment of breast cancer. But
there is still a lot of uncertainty about kaempferol acting as a drug for
clinical treatment of breast cancer. The factors include how to improve
bioavailability, enhance activity, construct targeted drug delivery
system etc. These situations need to be addressed through the joint
efforts of different professional scientists around the world.
Ethical approval and consent to participate
The authors have no ethical conflicts to disclose.
Consent for publication
All authors reviewed and approved the manuscript.
Availability of data and material
All data generated during this study are included in this published
article.
Competing interests
The authors declare that there are no conflicts of interest.
Funding
This work was supported by the Natural Science Foundation of
Guangxi Zhuang Autonomous Region (Grant
No.2018GXNSFBA281043), the Guangxi first-class discipline construc-
tion project of Guangxi University of Chinese Medicine (Grant
No.2018XK062) and the Development Program of High-level Talent
Team under Qihuang Project of Guangxi University of Chinese
Medicine (Grant No.2018005).
Authors’ contributions
Gang Fang initiated the study; Xueni Wang and Yuting Yang wrote
the manuscript; Xueni Wang draw the figures; Yating An and Gang Fang
revised the manuscript.
Acknowledgements
We thank Prof. Pang (Yuzhou Pang) of Guangxi University of
Chinese Medicine for his critical comments.
References
[1] F.-J. He, J.-Q. Chen, Consumption of soybean, soy foods, soy isoflavones and breast
cancer incidence: differences between Chinese women and women in Western
countries and possible mechanisms, Food Sci. Hum. Wellness 2 (3-4) (2013)
X. Wang, et al.
146–161.
[2] C.E. DeSantis, J. Ma, A. Goding Sauer, L.A. Newman, A. Jemal, Breast cancer sta-
tistics, 2017, racial disparity in mortality by state, CA Cancer J. Clin. 67 (6) (2017)
439–448.
[3] Adrienne G. Waks, E.P. Winer, Breast Cancer treatment, JAMA 321 (3) (2019) 316.
[4] M. Abotaleb, P. Kubatka, M. Caprnda, E. Varghese, B. Zolakova, P. Zubor, et al.,
Chemotherapeutic agents for the treatment of metastatic breast cancer: an update,
Biomed. Pharmacother. 101 (2018) 458–477.
[5] M. Akram, M. Iqbal, M. Daniyal, A.U. Khan, Awareness and current knowledge of
breast cancer, Biol. Res. 50 (1) (2017) 33.
[6] L. Del Mastro, M. Lambertini, C. Bighin, A. Levaggi, A. D’Alonzo, S. Giraudi, et al.,
Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer pa-
tients, Expert Rev. Anticancer Ther. 12 (11) (2012) 1391–1405.
[7] J.L. Blum, P.J. Flynn, G. Yothers, L. Asmar, C.E. Geyer Jr., S.A. Jacobs, et al.,
Anthracyclines in early breast Cancer: the ABC Trials-USOR 06-090, NSABP B-46-I/
USOR 07132, and NSABP B-49 (NRG oncology), J. Clin. Oncol. 35 (23) (2017)
2647–2655.
[8] G. Yang, S. Nowsheen, K. Aziz, A.G. Georgakilas, Toxicity and adverse effects of
Tamoxifen and other anti-estrogen drugs, Pharmacol. Ther. 139 (3) (2013)
392–404.
[9] S. Mallick, R. Benson, P.K. Julka, Breast cancer prevention with anti-estrogens:
review of the current evidence and future directions, Breast cancer 23 (2) (2016)
170–177.
[10] A. Jameera Begam, S. Jubie, M.J. Nanjan, Estrogen receptor agonists/antagonists in
breast cancer therapy: a critical review, Bioorg. Chem. 71 (2017) 257–274.
[11] Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-
analysis of the randomised trials, Lancet 386 (10001) (2015) 1341–1352.
[12] J. Foglietta, A. Inno, F. de Iuliis, V. Sini, S. Duranti, M. Turazza, et al.,
Cardiotoxicity of aromatase inhibitors in breast Cancer patients, Clin. Breast Cancer
17 (1) (2017) 11–17.
[13] J. Mu, D. Zhu, Z. Shen, S. Ning, Y. Liu, J. Chen, et al., The repressive effect of miR-
148a on Wnt/beta-catenin signaling involved in Glabridin-induced anti-angiogen-
esis in human breast cancer cells, BMC Cancer 17 (1) (2017) 307.
[14] Q. Zhou, W. Yin, Y. Du, J. Lu, For or against adjuvant trastuzumab for pT1a-bN0M0
breast cancer patients with HER2-positive tumors: a meta-analysis of published
literatures, PLoS One 9 (1) (2014) e83646.
[15] A. Yorulmaz, M. Dogan, F. Artuz, N. Zengin, Comparison of pigmentary side effects
of taxanes and anthracyclines: an onychoscopic evaluation, Cutan. Ocul. Toxicol. 36
(2) (2017) 135–139.
[16] J.V. McGowan, R. Chung, A. Maulik, I. Piotrowska, J.M. Walker, D.M. Yellon,
Anthracycline chemotherapy and cardiotoxicity, Cardiovasc. Drugs Ther. 31 (1)
(2017) 63–75.
[17] M.C. Bourgeois-Daigneault, L.E. St-Germain, D.G. Roy, A. Pelin, A.S. Aitken,
R. Arulanandam, et al., Combination of Paclitaxel and MG1 oncolytic virus as a
successful strategy for breast cancer treatment, Breast Cancer Res. 18 (1) (2016) 83.
[18] F. Zeng, R.J. Ju, L. Liu, H.J. Xie, L.M. Mu, W.L. Lu, Efficacy in treating lung me-
tastasis of invasive breast Cancer with functional vincristine plus dasatinib lipo-
somes, Pharmacology 101 (1-2) (2018) 43–53.
[19] L. Wang, X.E. Huang, J. Cao, Clinical study on safety of cantharidin sodium and
shenmai injection combined with chemotherapy in treating patients with breast
cancer postoperatively, Asian Pacific J. Cancer Prev. 15 (14) (2014) 5597–5600.
[20] A.M. Ranaware, K. Banik, V. Deshpande, G. Padmavathi, N.K. Roy, G. Sethi, et al.,
Magnolol: a neolignan from the Magnolia family for the prevention and treatment
of Cancer, Int. J. Mol. Sci. 19 (8) (2018).
[21] Y. Liu, W. Cao, B. Zhang, Y.Q. Liu, Z.Y. Wang, Y.P. Wu, et al., The natural com-
pound magnolol inhibits invasion and exhibits potential in human breast cancer
therapy, Sci. Rep. 3 (2013) 3098.
[22] Y. Zhou, Y. Bi, C. Yang, J. Yang, Y. Jiang, F. Meng, et al., Magnolol induces
apoptosis in MCF-7 human breast cancer cells through G2/M phase arrest and
caspase-independent pathway, Pharmazie 68 (9) (2013) 755–762.
[23] A.Y. Chen, Y.C. Chen, A review of the dietary flavonoid, kaempferol on human
health and cancer chemoprevention, Food Chem. 138 (4) (2013) 2099–2107.
[24] M.M. Mocanu, P. Nagy, J. Szollosi, Chemoprevention of breast Cancer by dietary
polyphenols, Molecules 20 (12) (2015) 22578–22620.
[25] A.J. Braakhuis, P. Campion, K.S. Bishop, Reducing breast Cancer recurrence: the
role of dietary polyphenolics, Nutrients 8 (9) (2016) 547.
[26] A. Barve, C. Chen, V. Hebbar, J. Desiderio, C.L. Saw, A.N. Kong, Metabolism, oral
bioavailability and pharmacokinetics of chemopreventive kaempferol in rats,
Biopharm. Drug Dispos. 30 (7) (2009) 356–365.
[27] V. Zabela, C. Sampath, M. Oufir, F. Moradi-Afrapoli, V. Butterweck, M. Hamburger,
Pharmacokinetics of dietary kaempferol and its metabolite 4-hydroxyphenylacetic
acid in rats, Fitoterapia 115 (2016) 189–197.
[28] L. Zhu, L. Xue, Kaempferol suppresses proliferation and induces cell cycle arrest,
apoptosis, and DNA damage in breast cancer cells, Oncol. Res. (2018).
[29] Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens,
Nat. Rev. Drug Discov. 10 (9) (2011) 671–684.
[30] A. Schulze, A.L. Harris, How cancer metabolism is tuned for proliferation and
vulnerable to disruption, Nature 491 (7424) (2012) 364–373.
[31] C. Azevedo, A. Correia-Branco, J.R. Araujo, J.T. Guimaraes, E. Keating, F. Martel,
The chemopreventive effect of the dietary compound kaempferol on the MCF-7
human breast cancer cell line is dependent on inhibition of glucose cellular uptake,
Nutr. Cancer 67 (3) (2015) 504–513.
[32] H. Hung, Inhibition of estrogen receptor alpha expression and function in MCF-7
cells by kaempferol, J. Cell. Physiol. 198 (2) (2004) 197–208.
[33] S.H. Kim, K.A. Hwang, K.C. Choi, Treatment with kaempferol suppresses breast
cancer cell growth caused by estrogen and triclosan in cellular and xenograft breast
5
Biomedicine & Pharmacotherapy 117 (2019) 109086
cancer models, J. Nutr. Biochem. 28 (2016) 70–82.
[34] X. Yi, J. Zuo, C. Tan, S. Xian, C. Luo, S. Chen, et al., Kaempferol, a flavonoid
compound from Gynura medica induced apoptosis and growth inhibition in Mcf-7
breast Cancer cell, Afr. J. Tradit. Complement. Altern. Med. 13 (4) (2016) 210–215.
[35] K. Brusselmans, R. Vrolix, G. Verhoeven, J.V. Swinnen, Induction of cancer cell
apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase
activity, J. Biol. Chem. 280 (7) (2005) 5636–5645.
[36] W. Liao, L. Chen, X. Ma, R. Jiao, X. Li, Y. Wang, Protective effects of kaempferol
against reactive oxygen species-induced hemolysis and its antiproliferative activity
on human cancer cells, Eur. J. Med. Chem. 114 (2016) 24–32.
[37] J. Huang, H. Li, G. Ren, Epithelial-mesenchymal transition and drug resistance in
breast cancer (Review), Int. J. Oncol. 47 (3) (2015) 840–848.
[38] G.A. Lee, K.C. Choi, K.A. Hwang, Kaempferol, a phytoestrogen, suppressed tri-
closan-induced epithelial-mesenchymal transition and metastatic-related behaviors
of MCF-7 breast cancer cells, Environ. Toxicol. Pharmacol. 49 (2017) 48–57.
[39] E.S. Radisky, D.C. Radisky, Matrix metalloproteinases as breast cancer drivers and
therapeutic targets, Front. Biosci. Landmark Ed. (Landmark Ed) 20 (2015)
1144–1163.
[40] C. Padala, M.A. Tupurani, K. Puranam, S. Gantala, N. Shyamala, M.S. Kondapalli,
et al., Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and ge-
latinase-B (MMP9) gene polymorphisms in breast cancer, PLoS One 12 (9) (2017)
e0184448.
[41] C. Chu, X. Liu, X. Bai, T. Zhao, M. Wang, R. Xu, et al., MiR-519d suppresses breast
cancer tumorigenesis and metastasis via targeting MMP3, Int. J. Biol. Sci. 14 (2)
(2018) 228–236.
[42] H. Yang, J. Liang, J. Zhou, J. Mi, K. Ma, Y. Fan, et al., Knockdown of RHOC by
shRNA suppresses invasion and migration of cholangiocellular carcinoma cells via
inhibition of MMP2, MMP3, MMP9 and epithelial-mesenchymal transition, Mol.
Med. Rep. 13 (6) (2016) 5255–5261.
[43] K. Phromnoi, S. Yodkeeree, S. Anuchapreeda, P. Limtrakul, Inhibition of MMP-3
activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line
by bioflavonoids, Acta Pharmacol. Sin. 30 (8) (2009) 1169–1176.
[44] C. Li, Y. Zhao, D. Yang, Y. Yu, H. Guo, Z. Zhao, et al., Inhibitory effects of
kaempferol on the invasion of human breast carcinoma cells by downregulating the
expression and activity of matrix metalloproteinase-9, Biochem. Cell Biol. 93 (1)
(2015) 16–27.
[45] L. Carey, E. Winer, G. Viale, D. Cameron, L. Gianni, Triple-negative breast cancer:
disease entity or title of convenience? Nat. Rev. Clin. Oncol. 7 (12) (2010) 683–692.
[46] C.A. Hudis, L. Gianni, Triple-negative breast cancer: an unmet medical need,
Oncologist 16 (Suppl 1) (2011) 1–11.
[47] A.G. Waks, E.P. Winer, Breast Cancer treatment: a review, Jama 321 (3) (2019)
288–300.
[48] S. Li, T. Yan, R. Deng, X. Jiang, H. Xiong, Y. Wang, et al., Low dose of kaempferol
suppresses the migration and invasion of triple-negative breast cancer cells by
downregulating the activities of RhoA and Rac1, Onco. Ther. 10 (2017) 4809–4819.
[49] Y. Yang, Y. Wang, T. Wang, X. Jiang, L. Wang, Screening active components of
modified Xiaoyao powder as NRF2 agonists, Cell Biochem. Funct. 35 (8) (2017)
518–526.
[50] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36
cancers in 185 countries, CA Cancer J. Clin. (2018).
[51] M. Messina, Impact of soy foods on the development of breast Cancer and the
prognosis of breast Cancer patients, Forsch. Komplementarmed. 23 (2) (2016)
75–80.
[52] C.B. Magne Nde, S. Zingue, E. Winter, T.B. Creczynski-Pasa, T. Michel,
X. Fernandez, et al., Flavonoids, breast Cancer Chemopreventive and/or che-
motherapeutic agents, Curr. Med. Chem. 22 (30) (2015) 3434–3446.
[53] M.T. Yasuda, H. Sakakibara, K. Shimoi, Estrogen- and stress-induced DNA damage
in breast cancer and chemoprevention with dietary flavonoid, Genes Environ. 39
(1) (2017) 10.
[54] Y.S. Qian, S. Ramamurthy, M. Candasamy, M. Shadab, R.H. Kumar, V.S. Meka,
Production, characterization and evaluation of kaempferol nanosuspension for
improving oral bioavailability, Curr. Pharm. Biotechnol. 17 (6) (2016) 549–555.
[55] W. Xu, M. Wen, J. Yu, Q. Zhang, N.E. Polyakov, A.V. Dushkin, et al.,
Mechanochemical preparation of kaempferol intermolecular complexes for enhan-
cing the solubility and bioavailability, Drug Dev. Ind. Pharm. 44 (12) (2018)
1924–1932.
[56] M. Colombo, G. de Lima Melchiades, L.R. Michels, F. Figueiro, V.L. Bassani,
H.F. Teixeira, et al., Solid dispersion of kaempferol: formulation development,
characterization, and oral bioavailability assessment, AAPS PharmSciTech 20 (3)
(2019) 106.
[57] A. Kapinova, P. Stefanicka, P. Kubatka, P. Zubor, S. Uramova, M. Kello, et al., Are
plant-based functional foods better choice against cancer than single phytochem-
icals? A critical review of current breast cancer research, Biomed. Pharmacother. 96
(2017) 1465–1477.
[58] C.Y. Wang, X.Y. Bai, C.H. Wang, Traditional Chinese medicine: a treasured natural
resource of anticancer drug research and development, Am. J. Chin. Med. (Gard
City N Y) 42 (3) (2014) 543–559.
[59] P. Kubatka, A. Kapinova, M. Kello, P. Kruzliak, K. Kajo, D. Vybohova, et al., Fruit
peel polyphenols demonstrate substantial anti-tumour effects in the model of breast
cancer, Eur. J. Nutr. 55 (3) (2016) 955–965.
[60] M.L. Ackland, S. van de Waarsenburg, R. Jones, Synergistic antiproliferative action
of the flavonols quercetin and kaempferol in cultured human cancer cell lines, In
Vivo (Brooklyn) 19 (1) (2005) 69–76.
[61] H. Luo, M.K. Daddysman, G.O. Rankin, B.H. Jiang, Y.C. Chen, Kaempferol enhances
cisplatin’s effect on ovarian cancer cells through promoting apoptosis caused by
X. Wang, et al.
down regulation of cMyc, Cancer Cell Int. 10 (2010) 16.
[62] S. Zhang, X. Yang, M.E. Morris, Combined effects of multiple flavonoids on breast
cancer resistance protein (ABCG2)-mediated transport, Pharm. Res. 21 (7) (2004)
1263–1273.
[63] C.Y. Beh, C.W. How, J.B. Foo, J.N. Foong, G.T. Selvarajah, A. Rasedee,
Development of erythropoietin receptor-targeted drug delivery system against
breast cancer using tamoxifen-loaded nanostructured lipid carriers, Drug Des.
Devel. Ther. 11 (2017) 771–782.
Biomedicine & Pharmacotherapy 117 (2019) 109086
[64] T. Liang, Z. Yao, J. Ding, Q. Min, L. Jiang, J.J. Zhu, Cascaded aptamers-governed
multistage drug-delivery system based on biodegradable envelope-type nanovehicle
for targeted therapy of HER2-Overexpressing breast Cancer, ACS Appl. Mater.
Interfaces 10 (40) (2018) 34050–34059.
[65] M. Wang, W. Liu, Y. Zhang, M. Dang, Y. Zhang, J. Tao, et al., Intercellular adhesion
molecule 1 antibody-mediated mesoporous drug delivery system for targeted
treatment of triple-negative breast cancer, J. Colloid Interface Sci. 538 (2019)
630–637.