Journal of Ethnopharmacology 314 (2023) 116575

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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Advances in autophagy modulation of natural products in cervical cancer

Tao Tao a, Ping Zhang b, Zhi Zeng a, Min Wang a, *
a
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
b
Department of Obstetrics and Gynecology, Shenyang Women’s and Children’s Hospital, Shenyang, Liaoning Province, China

A R T I C L E I N F O A B S T R A C T

Keywords: Ethnopharmacological relevance: Natural products play a critical role in drug development and is emerging as a
Natural products potential source of biologically active metabolites for therapeutic intervention, especially in cancer therapy. In
Autophagy recent years, there is increasing evidence that many natural products may modulate autophagy through various
Cervical cancer
signaling pathways in cervical cancer. Understanding the mechanisms of these natural products helps to develop
Alkaloids
Flavonoids
medications for cervical cancer treatments.
Aim of the study: In recent years, there is increasing evidence that many natural products may modulate auto­
phagy through various signaling pathways in cervical cancer. In this review, we briefly introduce autophagy and
systematically describe several classes of natural products implicated in autophagy modulation in cervical
cancer, hoping to provide valuable information for the development of cervical cancer treatments based on
autophagy.
Materials and methods: We searched for studies on natural products and autophagy in cervical cancer on the
online database and summarized the relationship between natural products and autophagy modulation in cer­
vical cancer.
Results: Autophagy is a lysosome-mediated catabolic process in eukaryotic cells that plays an important role in a
variety of physiological and pathological processes, including cervical cancer. Abnormal expression of cellular
autophagy and autophagy-related proteins has been implicated in cervical carcinogenesis, and human papillo­
mavirus infection can affect autophagic activity. Flavonoids, alkaloids, polyphenols, terpenoids, quinones, and
other compounds are important sources of natural products that act as anticancer agents. In cervical cancer,
natural products exert the anticancer function mainly through the induction of protective autophagy.
Conclusions: The regulation of cervical cancer autophagy by natural products has significant advantages in
inducing apoptosis, inhibiting proliferation, and reducing drug resistance in cervical cancer.

cervical cancer.
Autophagy is a lysosome-mediated catabolic process in eukaryotic
1. Introduction
cells that plays an important role in a variety of physiological and
pathological processes (Tabibzadeh, 2023). Many studies have
Cervical cancer has become the fourth most common malignancy
confirmed that abnormal expression of cellular autophagy and
affecting women’s health worldwide. According to the latest statistics
autophagy-related proteins is closely associated with cervical carcino­
from the GLOBOCAN database, more than 600,000 women have been
genesis and that HPV infection can affect autophagic activity (Ara­
diagnosed with cervical cancer in 2020, resulting in 340,000 deaths
nda-Rivera et al., 2021). Autophagy is a central element of the
worldwide (Sung et al., 2021). Currently, persistent infection with
integrated stress response and can be stimulated to maintain intracel­
high-risk human papillomavirus (HPV) is considered a key factor in the
lular homeostasis under conditions such as starvation, hypoxia, and
development and progression of cervical squamous intraepithelial le­
cellular damage occur. Autophagy is responsible for the removal of not
sions and cervical cancer (Giannone et al., 2022). With the introduction
only abnormal intracellular components but also invading pathogens,
of cervical cancer screening and vaccination, the incidence of cervical
including viruses and bacteria, and other infectious factors (Klionsky
cancer has decreased, but the mortality rate is still high, so it is impor­
et al., 2021). However, the mechanisms underlying autophagy and HPV
tant to find new mechanisms, new targets, and new ways to treat

* Corresponding author. Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, She­
nyang, Liaoning Province, China.
E-mail address: wm21st@126.com (M. Wang).

https://doi.org/10.1016/j.jep.2023.116575
Received 15 March 2023; Received in revised form 23 April 2023; Accepted 1 May 2023
Available online 2 May 2023
0378-8741/© 2023 Elsevier B.V. All rights reserved.
T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

by regulating autophagy. These products are of interest for their po­

A list of abbreviations tential activity against many types of cancer, including prostate,
pancreatic, liver, breast, cervical, and ovarian cancers (Chan et al.,
(HPV) human papillomavirus 2023a). In cervical cancer, natural products play a critical role in
(ATG) autophagy-associated gene interfering with HPV infection, promoting apoptosis of cervical cancer
(ULK) Unc-51-like autophagy activating kinase cells, and enhancing cisplatin sensitivity (Khairkhah et al., 2022). This
(PAS) phagophore assembly site; review will describe several classes of natural products that are thera­
(PE) phosphatidylethanolamine; peutically relevant due to autophagy regulation in cervical cancer,
(HSPG) heparan sulfate proteoglycan hoping to provide a reference value for the treatment of cervical cancer.
(PTEN) phosphatase and tensin homolog
(cGAS) cyclic GMP-AMP synthase 2. What is autophagy?
(cGAMP) cyclic GMP-AMPP
(STING) stimulator of interferon genes Autophagy is a self-renewal process that occurs in response to
(TBK1) TANK binding kinase 1 various forms of cellular stress, including infection, hypoxia, starvation,
(ATR) ataxia telangiectasia and RAD3-related and endoplasmic reticulum stress. Organelles and intracellular proteins
(ATM) ataxia-telangiectasia mutated are captured by cells and transported lysosomes for degradation. Auto­
(CHK1) checkpoint kinase 1 phagic degradation products are exported from the lysosomes to the
(GTP) Green tea polyphenol cytoplasm for recycling (Shu et al., 2023). The first genetic screen for
(EGCG) (− )-Epigallocatechin-3-gallate autophagy was performed by Yoshinori Ohsumi, who analyzed the
(DOX) doxorubicin process in yeast and identified 15 autophagy-associated genes (ATGs)
(FOXM1) forkhead box M1 (Tsukada and Ohsumi, 1993). More than 30 ATGs have now been
(CIN) cervical intraepithelial neoplasm identified. The autophagic pathway is often divided into the following
stages: initiation, vesicle formation, autophagic membrane elongation,
fusion with lysosomes, and degradation of intracellular products. Recent
studies have shown that autophagy can selectively eliminate harmful
infection remain unclear. cellular contents, including protein aggregates, dysfunctional organ­
Recent studies have shown that natural products have unique ad­ elles, and invading pathogens, thus acting as a cell protector under
vantages in the prevention and treatment of cancer (Zhou et al., 2022). various environmental and metabolic stresses (Chen et al., 2023).
Natural products include volatile oils, esters, glycosides, flavonoids, Autophagy has been implicated in heart disease, immunity, metabolic
phenols, and alkaloids that have been shown to exert anti-cancer effects diseases, cancer, and neurodegeneration. In cancer, autophagy plays a

Fig. 1. Schematic diagram of the autophagy process in mammalian cells.

The mTORC1 contributes to the initiation of autophagy, integrating upstream signals such as the PI3K/Akt pathway, AMPK, P53, and the Bcl-2 protein family. The
ULK1 complex induces vesicle nucleation and translocates to a characteristic endoplasmic reticulum structure called an omegasome, where it phosphorylates PI3KC3
complex I to produce PI3P in the omegasome. Beclin-1 is phosphorylated by ULK1 and acts as a scaffold for the PI3KC3 complex I, facilitating the localization of
autophagy proteins to the phagophore. ATG9 is a transmembrane protein involved in the early phase of phagophore formation. PI3P recruits specific autophagy
effectors, such as WIPIs (mammalian homolog of yeast Atg18) and zinc finger FYVE-type containing 1. WIPIs bind directly to ATG16L1 under the regulation of the
Ub-like conjugation system to form the ATG12-ATG5-ATG16L1 complex and LC3 (mammalian homolog of yeast Atg8)-PE binding. Finally, the isolation membrane is
elongated and closed to form the autophagosome. This binding reaction results in the conversion of LC3I to LC3II. As the autophagosome matures, it sheds the ATGs
and fuses with the lysosome to produce autophagolysosome. The resulting monomer molecules (such as amino acids and lipids) are returned to the cytoplasm for
reuse. The pointed and blunt arrowheads indicate activating and inhibitory interactions, respectively. mTORC1, mTOR complex 1; PI3P, phosphatidylinositol-3-
phosphate; PE, phosphatidylethanolae; Ub, ubiquitin.

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T. Tao et al.
dual role. During tumorigenic stress, autophagy removes toxic unfolded
proteins and oncogenic protein substrates, thereby inhibiting tissue
damage and genomic instability. Conversely, increased autophagic flux
is capable of sustaining tumor cell proliferation and high metabolic
demand after tumor formation (Lee et al., 2023). This ‘double-edged
sword’ has made the autophagic pathway a focus of research.
Autophagy initiation begins with the activation of the Unc-51-like
autophagy activating kinase (ULK) complex, including ATG13,
FIP200, ULK1, and ULK2, leading to the recruitment of ATGs to phag­
ophore assembly sites (PASs). Further activation of PI3KC3 complex I,
including Atg14, p150 (mammalian homolog of yeast VPS15), VPS34,
and Beclin-1 (mammalian homolog of yeast Atg6), and isolation to form
a ring-shaped structure called the autophagosome (Dikic and Elazar,
2018). The ATG5-ATG12 complex then binds to ATG16, which stretches
the autophagosome membrane into a spherical shape. ATG4 enzymati­
cally cleaves LC3 (an Atg8 family protein) to produce cytoplasmic LC3I,
which binds to the lipid phosphatidylethanolamine (PE) to form LC3II
and is recruited to the autophagosome membrane (Lamb et al., 2013).
Subsequently, lysosomes fuse with autophagosomal membranes to form
autophagic lysosomes, which release acid hydrolases and then degrade
the contents, thus enabling metabolic pathways and renewal of organ­
elles in the cell. In addition, SQSTM1 (also known as P62), an auto­
phagic modifier of the LC3 family, acts as a bridge between degraded
cargo proteins and autophagosomes and can be used as a measure of
autophagic flux (Jiang and Mizushima, 2015). A schematic representa­
tion of autophagic pathway in mammalian cells is shown in Fig. 1.
3. Effect of HPV infection on autophagy
HPV is an envelope-free double-stranded DNA virus consisting of a
viral genome and capsid proteins (L1 and L2), which are divided into
early coding regions (E1, E2, E4, E5, E6, and E7), late coding regions (L1
and L2), and long control regions, while the E5, E6, and E7 genes encode
the viral E5, E6, and E7 oncoproteins (Cosper et al., 2021). Binding and
infection of HPV can occur in basal keratin-forming cells at the site of
microtrauma of the genital tract caused by sexual intercourse, the virus
binds and interacts with heparan sulfate proteoglycans (HSPGs) on the
cell surface via the L1 protein, causing conformational changes in the L2
protein, hydrolysis, and subsequent endocytosis into the host cell
(Groves and Coleman, 2015). The interaction between viruses and
HSPGs can trigger various signaling pathways associated with HPV
infection, and the internalization process can activate the mTOR
pathway-dependent autophagy inhibition process. HPV attachment to
host cells interacts with epidermal growth factor receptors on the
plasma membrane, causing Akt phosphorylation, phosphatase and ten­
sin homolog (PTEN) inactivation, and activation of downstream mTOR
and triggering mTORC1 substrate, thereby inhibiting cellular auto­
phagy, avoiding early clearance of the virus and increasing the likeli­
hood of HPV infection (Shin et al., 2019).
3.1. HPV infection affects the autophagy-related immune response
The innate immune response is a key host defense and is the first line
of defense against pathogens. HPV has been shown to evade clearance
by suppressing innate immunity (Della Fera et al., 2021). As a cyto­
plasmic DNA receptor, cyclic GMP-AMP synthase (cGAS) recognizes and
is activated by HPV viral DNA, producing cyclic GMP-AMPP (cGAMP).
cGAMP binds to the stimulator of interferon genes (STING) located in
the endoplasmic reticulum. They then translocate to the Golgi appa­
ratus, recruit and activate TANK binding kinase 1 (TBK1) to stimulate
the interferon synthesis pathway, and induce the expression of inter­
feron and other cytokines to initiate the antiviral response (Yan et al.,
2023). Gui et al. found that STING also activates autophagy through a
pathway independent of TBK1, i.e., STING binds cGAMP and trans­
locates to the endoplasmic reticulum-Golgi intermediate to induce LC3
lipidation and autophagosome formation through a WIPI2 and
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Journal of Ethnopharmacology 314 (2023) 116575
ATG5-dependent pathway (Gui et al., 2019). In addition, the E7 protein
of HPV18 could bind to STING, inhibit the cGAS-STING pathway, and
antagonize viral DNA signaling (Lau et al., 2015). HPV18 can also
persistently inhibit type I interferon production via the cGAS-STING
pathway (Lo Cigno et al., 2020). These studies suggest that induction
of autophagy may be a primitive function of the cGAS-STING signaling
pathway, but there is no evidence to confirm that sustained viral stim­
ulation can be achieved by inhibition of WIPI2- and ATG5-dependent
autophagic processes following the binding of STING to HPV
oncoproteins.
In HPV16-infected cells, high expression of E7 decreased STING
levels and increased LC3II levels, which could be partially reversed by
the application of autophagy inhibitors. In addition, E7 could further
induce autophagic degradation of STING and inhibit DNA virus-induced
immune activation by promoting the formation of NLRX1-centered
complexes (Luo X. et al., 2020). Taken together, these results suggest
that HPV may affect the infection process of viral DNA through auto­
phagy, thereby inhibiting the innate immune response and facilitating
the maintenance of persistent viral infection.
The JAK/STAT pathway is a typical type I interferon-mediated
signaling pathway that induces antiviral responses. This pathway pro­
motes interferon response and induces STAT1/2-dependent autophagy
in a variety of cancer cell lines. For example, in Burkitt’s lymphoma
Daudi cells, type I interferon-induced autophagy in a STAT2-dependent
manner (Schmeisser et al., 2013); in chronic myeloid leukemia cells,
IFN-α-activated JAK1 and STAT1 promoted Beclin-1 production (Zhu
et al., 2013). According to Gusho et al., the E6 and E7 proteins reduced
the expression level of STAT1 and if STAT1 expression is restored, the
process of HPV genome amplification would be halted (Gusho and Lai­
mins, 2021). However, there is no direct evidence that HPV persistence
status is associated with the inhibition of the STAT1/2-dependent
autophagy process. STAT1 and autophagy appear to be bidirectional
in HPV-infected cells. The results of Wu et al. showed that HPV16 copy
number and STAT1 expression level were positively associated with
lesion progression in cervical cancer tissues (Wu et al., 2020). In
contrast, the results of Rajkumar et al. showed that STAT1 was increased
in CIN1/2, decreased in CIN3/in situ carcinoma, and significantly
increased in invasive carcinoma (Rajkumar et al., 2011), suggesting that
STAT1 may play a protective role in the early stage of infection and act
as a pro-cancer in the invasive stage. Meanwhile, the results of
Aranda-Rivera et al. showed that high-risk HPV inhibits autophagy in
the early stage of cancer to prevent viral clearance and induces auto­
phagy in the advanced stage to provide energy to cancer cells (Ara­
nda-Rivera et al., 2021). The association and impact of STAT with
autophagy during persistent HPV infection and cellular transformation
need to be elucidated by further studies.
Type I interferons also affect the PI3K/Akt/mTOR pathway. Xie et al.
showed that 5-aminolevulinic acid photodynamic therapy induced LC3II
and p62 expression by inhibiting the PI3K/Akt/mTOR pathway and
reduced viral load in HeLa cells by promoting autophagy (Xie et al.,
2019). Thus, HPV may regulate autophagy by modulating the down­
stream signaling pathway of type I interferon to achieve persistent HPV
infection.
3.2. HPV infection affects the autophagy-related DNA damage repair
Among DNA damage repair pathways, HPV primarily affects ataxia
telangiectasia and RAD3-related (ATR) and ataxia-telangiectasia
mutated (ATM) proteins, which block the cell cycle and inhibit DNA
damage repair or promote apoptotic senescence of damaged cells
(Gusho and Laimins, 2021). The abnormal DNA produced by
single-strand breaks activates ATR, which phosphorylates cell cycle
checkpoint kinase 1 (CHK1) and activates other downstream factors.
Activation of the ATR pathway is critical for the maintenance and
amplification of the HPV genome (Luo Y. et al., 2020). Liu et al. found
that DNA damage phosphorylates the small GTPase RhoB downstream
T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

of ATR/CHK1 and enhances its interaction with TSC2, which subse­ Table 1
quently translocates the RhoB/TSC complex to the lysosome and inhibits Autophagy regulators of Flavonoids.
mTORC1 activity to initiate autophagy (Liu et al., 2018). HPV8 protein Natural product Cell Effect on Mechanism Reference
can manipulate CHK1 levels through the autophagic pathway, thereby type Autophagy
inhibiting activation of the ATR pathway (Akgül et al., 2019). Hong Nujiangexanthone HeLa Induction 1) decrease in Feng et al.
et al. demonstrated that in HPV-positive cells, activation of ATR trig­ A cells membrane (2021)
gered selective autophagy protein p62 phosphorylation, mediated protein LAMP1
autophagic degradation of GATA4, suppressed expression of many in­ expression
2) increase in LC3II
flammatory genes in the immune response, and reduced IFN-κ produc­ expression
tion, leading to HPV viral amplification (Hong et al., 2020). Taken Apigenin HeLa Induction increase in Beclin-1 Kayacan
together, these data suggest that HPV infection affects cells expression et al.
autophagy-related DNA damage repair and the differences may be (2021)
Chalcone HeLa Induction 1) increase in LC3II (Nedungadi
related to the functional structure of E6 and E7 proteins in different
and and Beclin-1 et al., 2021;
isoforms. SiHa expressions Solano
cells 2) inhibition of the et al., 2013;
4. Natural products that regulate autophagy in cervical cancer phosphorylation Tsai et al.,
of PI3K/Akt 2015)
pathway
Natural products have had the important therapeutic potential for Quercetin HeLa Induction 1) decrease in p- (Bądziul
the prevention or treatment of human diseases for thousands of years cells mTOR expression et al., 2014;
(Goel et al., 2023). It plays a critical role in drug development and is 2) increase in LC3II Luo et al.,
emerging as a potential source of biologically active metabolites for and Beclin-1 2016;
expressions Wang et al.,
therapeutic intervention, especially in cancer therapy (Garg et al.,
2016)
2023). Flavonoids, alkaloids, polyphenols, terpenoids, quinones, and
other compounds are important sources of natural products that act as
anticancer agents (Chan et al., 2023b). In cervical cancer, natural skin cancer has been extensively studied. From various studies, Apigenin
products exert the anticancer function mainly through the induction of downregulated the expression of inflammatory cytokines by suppressing
protective autophagy. Here, we summarized some important natural the NF-κB, MAPK, and AP-1 signaling pathways in keratinocytes.
products that mediate autophagy in cervical cancer, hoping to provide Meanwhile, Apigenin induced autophagy by inhibiting mTOR activity
the theoretical basis for cervical cancer therapy. and inactivating PKC and Akt activities (Jangdey et al., 2017). Despite
the lack of direct evidence of effect, the combination of Apigenin and
4.1. Flavonoids Curcumin, which is a naturally occurring compound, increased the
expression of genes related to autophagic cell death, including ATG12,
4.1.1. Nujiangexanthone A DAPK, ATG5, Beclin-1, and Bcl-xL (Kayacan et al., 2021). These data
Nujiangexanthone A is a bioactive compound isolated from Garcinia indicated that co-treatment with Apigenin and Curcumin had significant
nujiangensis C.Y.Wu & Y.H.Li. Xia et al. obtained the novel prenylated and synergistic effects on inhibiting cell growth in cervical cells by
xanthone, nujiangexanthones A, by bioassay-directed fractionation of inducing autophagy-related cell death.
G. nujiangensis (Xia et al., 2012). The anti-allergic function of Nujian­
gexanthone A was demonstrated by Lu et al. who found that Nujian­ 4.1.3. Chalcone
gexanthone A inhibited the levels of inflammatory cytokines and IgE in Chalcone is a natural product found in Tilia tomentosa Moench,
the ovalbumin-induced asthma model (Lu et al., 2016). The anticancer Alpinia hainanensis K.Schum., and other organisms. Previous studies
effects of Nujiangexanthone A were discovered in liver cancer and cer­ have shown that chalcones and their derivatives have anticancer, anti­
vical cancer. In liver cancer, Nujiangexanthone A inhibited the migra­ microbial, and anti-inflammatory activities (Katsori and
tion, invasion, and metastasis of hepatocellular carcinoma cells both in Hadjipavlou-Litina, 2009; Nowakowska, 2007). Three types of Chal­
vitro and in vivo (Zhang et al., 2021). The actin-binding protein cones have been reported to modulate autophagy in cervical cancer. The
cofilin1-mediated dynamics of the actin cytoskeleton is involved in products of the reaction between bis-chalcones and 6-amine-1,3-dime­
Nujiangexanthone A-regulated migration and epithelial-mesenchymal thyl-uracil induced the conversion of LC3BII, which was not
transition in liver cancer. In cervical cancer, Nujiangexanthone A also completely abolished by the autophagy inhibitor spautin-1 (Solano
acts as an anticancer drug. It induced the accumulation of GFP-LC3 and et al., 2013). Licochalcone A is a characteristic chalcone of licorice
YFP-Parkin puncta (Feng et al., 2021). In HeLa cells, Nujiangexanthone (Kwon et al., 2008). SiHa cells treated with Licochalcone A resulted in a
A induced lysosomal degradation and colocalization of autophago­ dose-dependent increase in the expression of LC3II (Tsai et al., 2015). A
somes, which was reversed by the knockdown of ATG7 (Feng et al., trend toward increased expression of protein levels of Atg12, Atg5, Atg7,
2021). These data indicated that Nujiangexanthone A inhibited cervical and Beclin1 was also observed in Licochalcone A-treated SiHa cells (Tsai
cancer cell proliferation by promoting mitochondrial autophagy. In et al., 2015). Inhibition of the phosphorylation of the PI3K/Akt pathway
addition, another xanthone isolated from G. nujiangensis, isojacareubin, was considered as the mechanism in Licochalcone A-induced autophagy
was reported to inhibit proliferation and induce apoptosis of ovarian (Tsai et al., 2015). In HeLa cells, the derivative of chalcones,
cancer cells (Tang et al., 2020). The regulatory mechanism may be the 2’-hydroxy-retrochalcone, increased the expression of LC3II in a time-
blockade of the PI3K/AKT signaling pathway, which is also a critical and dose-dependent manner (Nedungadi et al., 2021). It impaired the
pathway in autophagy. Whether isojacareubin regulates autophagy in autophagic flux and led to cell death (Nedungadi et al., 2021). These
cancer deserves further investigation. studies prove the anti-cancer activities of Chalcones in cervical cancer
and other types of Chalcones have the potential to be further tested for
4.1.2. Apigenin their application in cervical cancer treatment.
Apigenin is a plant-derived flavonoid that shows promise as a che­
mopreventive agent for skin cancer. It is abundant in fruits and vege­ 4.1.4. Quercetin
tables. In recent years, the antiproliferative, anti-inflammatory, and Extracts of Quercetin are used to treat or prevent several conditions
antimetastatic activities of Apigenin have been discovered (Thomas including infections, rheumatic diseases, hypercholesterolemia, cardio­
et al., 2023; Yoon et al., 2023). The suppressive activity of Apigenin on vascular disease, and cancer (Shabir et al., 2022). Exposure of HeLa cells

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T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

Fig. 2. (A) The autophagy regulators of flavonoids. (B) The autophagy regulators of alkaloids.

to the 50 μM concentration of Quercetin for 48 h significantly reduced synthesized. Among them, MASM have an anti-inflammatory property in
cell viability to approximately 60% (Bądziul et al., 2014). Quercetin vitro (Hu et al., 2010). MASM induced an accumulation of LC3II in HeLa
induced autophagy in HeLa cells by increasing Beclin-1 expression cells, and it significantly inhibited the phosphorylation of Akt in a
(Bądziul et al., 2014). Using transmission electron microscopy, Wang dose-dependent manner, indicating that MASM could induce autophagy
et al. observed a large number of vacuoles in the cytoplasm, indicating by inhibiting the PI3K/Akt/mTOR signaling pathway (Zou et al., 2019).
that lysosomal autophagy was generated (Wang et al., 2016). Luo et al.
loaded gold-quercetin into poly (DL-lactide-co-glycolide) nanoparticles 4.2.2. Lamellarin
onto cervical cancer cells, and found that quercetin nanoparticles sup­ As marine alkaloids, Lamellarins contain fused 14-phenyl-6H-[1]
pressed mTOR regulated by the PI3K/AKT signaling pathway and benzopyrano [4’,3’:4,5] pyrrolo [2,1-a] isoquinoline or unfused 3,4-dia­
inhibited the proliferation of HeLa cells (Luo et al., 2016). Table 1 and rylpyrrole-2-carboxylate ring systems (Fukuda et al., 2020). Many of
Fig. 2A shows the autophagy regulators of flavonoids. them have the activities including anti-HIV-1 activity, protein kinase
inhibition, topoisomerase I inhibition, and, potent cytotoxicity (Bailly,
2015). Acute cytotoxicity induced by Lamellarin resulted in largely
4.2. Alkaloids
unaltered steady-state levels of PTEN-induced kinase-1, mitochondrial
heat shock protein 60, and prohibitin-1 (Sopha et al., 2021). Lamellarin
4.2.1. Matrine
also induced further increased LC3II accumulation in HeLa cells, sug­
Matrine is a natural product found in Daphniphyllum oldhamii K.
gesting that it activates autophagic flux and/or inhibits autophagic
Rosenth., Sophora davidii (Franch.) Pavol., and other organisms. It has a
degradation (Sopha et al., 2021). In addition, disruption of autophagy
variety of pharmacological effects, including anticancer activity and
by silencing ATG5 greatly enhanced HeLa cell apoptosis by Lamellarin,
action as a kappa opioid receptor and μ-receptor agonist (Sun Y. et al.,
although almost no effect on the final fate of cell death was observed
2022). An abundance of autophagosomes and autophagolysosomes was
(Sopha et al., 2021). These data indicate that autophagy could protect
observed in Matrine-treated SiHa and HeLa cells, and the expression of
cells from Lamellarin-mediated cytotoxicity, whereas its role becomes
LC3A/BII was significantly increased with increasing dose of Matrine
less pronounced after prolonged treatment.
and duration of treatment (Zhang F. et al., 2022). However, since
Matrine has low therapeutic efficacy, Matrine derivatives have been
4.2.3. Berberine
Berberine can be found in many botanical products, including oregon
Table 2 grape, barberry, and goldenseal, which has the properties of antioxidant
Autophagy regulators of Alkaloids.
and antimicrobial. Berberine has been used for a variety of conditions,
Natural Cell type Effect on Mechanism Reference including colon adenoma prevention, H. pylori infection, heart failure,
product Autophagy hyperlipidemia, diabetes, and obesity (Zhu et al., 2022). Many studies
Matrine HeLa and Induction 1) increase in LC3II (Zhang F. have confirmed that Berberine affects tumor cell development by
SiHa cells expression et al., 2022; inhibiting tumor cell growth and inducing apoptosis and cell cycle arrest
2) inhibition of Akt/ Zou et al.,
(Liu et al., 2019). Berberine induces autophagy and apoptosis through
mTOR signaling 2019)
pathway the p38 signaling pathway to inhibit the proliferation of human colon
Lamellarin HeLa Induction increase in LC3II Sopha et al. cancer cells as LC3 and ATG5 were upregulated (Zhang et al., 2017). The
cells expression (2021) oral bioavailability of Berberine is less than 5% due to absorption in­
Berberine CaSki Induction increase in Floriano et al.
hibition caused by P-glycoprotein efflux (Raghav et al., 2017). There­
and intracellular (2021)
HaCaT autophagosomes
fore, new formulations of nanoemulsion protocols have shown efficacy
cells in bypassing the P-glycoprotein efflux system (Kumar et al., 2015). In
Neferine HeLa and Induction 1) increase in LC3II Dasari et al. cervical cancer, Berberine nanoemulsions as photosensitizers in photo­
SiHa cells and Beclin-1 (2020) dynamic therapy induced autophagic processes in HaCaT and CaSki
expressions
cells, leading to autophagosome formation and cell death (Floriano
2) decrease in HPV
early genes (E6 et al., 2021).
and E7)

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T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

4.2.4. Neferine Baf-A1 reduced the degradation of autophagolysosome by blocking

Neferine is a natural product found in Nelumbo nucifera Gaertn.
Neferine has several pharmacological effects, including inhibition of the
proliferation of vascular smooth muscle cells, hypertrophic scar fibro­
blasts, and diabetes (Plazas et al., 2022). In cancer cells, Neferine shows
a reversal of multidrug resistance (Kadioglu et al., 2017), and it
dose-dependent inhibition of cell migration of both SiHa and HeLa cells
(Dasari et al., 2020). pEGFP-LC3 plasmid was transiently transfected
into both SiHa and HeLa cells to confirm whether LC3 was involved in
Neferine-induced autophagy. Results showed that the Neferine-treated
cells showed sharp green LC3 punctate dots in the cytoplasm, indi­
cating the accumulation of LC3II in Neferine-treated SiHa and HeLa cells
(Dasari et al., 2020). In addition, HPV genes (E6 and E7) were decreased
in cells treated with Neferine (Dasari et al., 2020). These studies sug­
gested that Neferine can be a potent anticancer agent for cervical cancer.
Table 2 and Fig. 2B shows the autophagy regulators of alkaloids.
4.3. Polyphenols
4.3.1. Green tea polyphenols
Green tea polyphenols (GTPs) are polyphenolic compounds extrac­
ted from green tea. They exhibit diverse antitumor, antioxidant, and
anti-inflammatory activities (Mokra et al., 2022). (− )-Epi­
gallocatechin-3-gallate (EGCG) and doxorubicin (DOX) are two major
components of GTP. In HeLa cells, EGCG and DOX induced autophagic
flux and accelerated the formation of autophagosomes (Chen et al.,
2020). GTP also increased autophagosomes and the LC3II/LC3I ratio in
HPV16 (+) immortalized human cervical epithelial cells (Tang et al.,
2022). After Nrf2 knockdown, fewer cells exhibited autophagosomes
upon GTP treatment, suggesting that GTP promotes autophagy and the
process needs the participation of Nrf2 (Tang et al., 2022). As reported,
p62 influences the Keap1 degradation induced by autophagy, while Nrf2
regulates the mRNA level of p62 (Bartolini et al., 2018). Thus, a positive
feedback loop has been established that regulates the interaction be­
tween autophagy and the Nrf2 signaling.
4.3.2. Curcumin
Curcumin is a phytopolylphenol pigment isolated from the plant
Curcuma longa L. with a variety of pharmacological properties. It has
been shown to significantly inhibit E6/E7 transcription and cervical
cancer cell proliferation (Mukherjee et al., 2017). Wang et al. showed
that 30 μM of Curcumin can induce autophagy in SiHa cells (Wang T.
et al., 2020). Autophagy was activated in SiHa cells under the combined
treatment of Baf-A1 and Curcumin, suggesting that Curcumin and
autophagy, thereby causing the accumulation of LC3II and p62 (Wang T.
et al., 2020). Meanwhile, treatment with a combination of apigenin and
curcumin showed a synergistic anti-tumor effect via cross-talk between
processes leading to apoptosis and autophagic cell death (Kayacan et al.,
2021). Kavya et al. synthesized a cationic amino acid polymer nano­
carrier encapsulated with Curcumin and treated with folic acid (Kavya
et al., 2022). In HeLa cells, the polymer nanocarrier induced autophagy
by increasing LC3II levels (Kavya et al., 2022).
4.3.3. 6-Shogaol
Shogaol is a natural product found in Flueggea suffruticosa (Pall.)
Baill., Zingiber zerumbet (L.) Sm., and other organisms. Among the sho­
gaols, 6-Shogaol exhibits antiproliferative activity in colon, pancreatic,
prostate, gastric, and leukemia cancer cells (Arcusa et al., 2022). In
human lung cancer, 6-Shogaol was observed to induce autophagy via the
inhibition of the Akt/mTOR pathway (Hung et al., 2009). In human
cervical cancer, 6-Shogaol inhibited cell proliferation by inducing G2/M
cell cycle arrest (Pei et al., 2021). It also induced autophagy in both
HeLa and SiHa cells by increasing the expression of LC3II and Beclin-1
(Pei et al., 2021). The protein expression levels of p-PI3K, p-Akt, and
p-mTOR were decreased by 6-Shogaol in a dose-dependent manner,
indicating that 6-Shogaol induced autophagy by downregulating the
PI3K/Akt/mTOR pathway (Pei et al., 2021).
4.3.4. Rosmarinic acid methyl ester
Rosmarinic acid methyl ester is a natural product found in Isodon
oresbius Kudô, Perilla frutescens var. frutescens, and other organisms. As a
derivative of rosmarinic acid, Rosmarinic acid methyl ester has several
biological effects, such as anti-inflammatory, anti-microbial, and anti­
allergic effects (Jamnani et al., 2023). In ovarian cancer cells, Rosmar­
inic acid methyl ester inhibited cell migration and invasion by
decreasing the expression of forkhead box M1 (FOXM1) target genes at
an mRNA level and the binding of FOXM1 to its target genes (Lim et al.,
2020). In cervical cancer, Rosmarinic acid methyl ester was reported to
be a potent inhibitor of the mTOR/S6K1 signaling pathway (Nam et al.,
2019). Rosmarinic acid methyl ester treatment of HeLa and SiHa cells
inhibited the activation of S6K1 and the S6K1 activity (Nam et al.,
2019). Meanwhile, in HeLa and SiHa cells, Rosmarinic acid methyl ester
treatment resulted in an elevation in lipidated LC3II (Nam et al., 2019).
4.3.5. Hispolon
Hispolon has been reported to possess pharmacological activities
such as antioxidant, anti-tumor, antiviral, anti-inflammatory,

Table 3
Autophagy regulators of polyphenols.
Natural product Cell type Effect on Mechanism Reference
Autophagy

Green Tea HeLa cells and HPV16 (+) immortalized Induction 1) increase in LC3II and Beclin-1 (Chen et al., 2020; Tang et al., 2022)
Polyphenols human cervical epithelial cells expressions
2) activation of Nrf2 Pathway
3) acceleration of autophagosome
formation
Curcumin HeLa and SiHa cells Induction increase in LC3II and Beclin-1 (Kavya et al., 2022; Kayacan et al., 2021;
expressions Wang T. et al., 2020)
6-Shogaol HeLa and SiHa cells Induction 1) decrease in p-PI3K, p-Akt, and p- Pei et al. (2021)
mTOR expressions
2) increase in LC3II expression
Rosmarinic acid HeLa and SiHa cells Induction increase in LC3II and ULK1 expressions Nam et al. (2019)
methyl ester
Hispolon HeLa and SiHa cells Induction increase in LC3II and Beclin-1 Hsin et al. (2017)
expressions
Resveratrol HeLa, CaSki, SiHa, C33A, and CaLo cells Induction 1) increase in lysosomal permeability (García-Zepeda et al., 2013; Hsu et al.,
2) promotion of autophagosome 2009)
formation
3) increase in LC3II expression
Carvacrol HeLa cells Induction increase in LC3II expression Potočnjak et al. (2018)

6
T. Tao et al.
Fig. 3. The autophagy regulators of polyphenols.
hepatoprotective, immunomodulatory, and anti-diabetic (Sarfraz et al.,
2020). In cancer, Hispolon has been confirmed to possess anti­
proliferative activity against glioblastoma, cervical cancer, breast can­
cer, nasopharyngeal cancer, lung cancer, prostate cancer, leukemia,
gastric cancer, bladder cancer, hepatocellular carcinoma, renal cancer,
and human epidermoid carcinoma cells (Sarfraz et al., 2020). In SiHa
and HeLa cells treated with Hispolon, the high dose of Hispolon reduced
cell viability by only 20% (Hsin et al., 2017). It increased LC3II
expression and acidic vesicular organelle development (Hsin et al.,
2017). In addition, chloroquine (the lysosomal inhibitor) blocked the
Hispolon-mediated LC3II turnover (Hsin et al., 2017). These data indi­
cated that Hispolon induced autophagiy in cervical cancer cells.
4.3.6. Resveratrol
Resveratrol is a plant polyphenol found in red grapes and has been
proposed as a treatment for hyperlipidemia and prevention of aging,
atherosclerosis, diabetes, and fatty liver (Planinc et al., 2022). In 2009,
Hsu et al. first found that Resveratrol induced GFP-LC3 aggregation as
well as increased the presence of LC3II and autophagosomes and that
Resveratrol also induced a decrease in lysosomal membrane perme­
ability (Hsu et al., 2009). In HeLa, CaLo, and C33A cells, an increased
lysosomal permeability was observed after Resveratrol treatment (Gar­
cía-Zepeda et al., 2013). Interestingly, the p53 expression was decreased
in HeLa and CaLo cells and increased in SiHa, CaSki, and C33A cells after
Resveratrol treatment (García-Zepeda et al., 2013). The expression of
p65 was decreased after Resveratrol treatment in all cell lines except
SiHa cells (García-Zepeda et al., 2013). These data indicated that
Resveratrol used different mechanisms to induce autophagy in cervical
cancer cells. The effects of HPV infection on Resveratrol treatment
deserve further investigation.
4.3.7. Carvacrol
Carvacrol is a natural product found in Xylopia aromatica Mart.,
Xylopia sericea A.St.-Hil., and other organisms. It has roles as a volatile
oil component, flavoring agent, antimicrobial agent, agrochemical, and
TRPA1 channel agonist (Imran et al., 2022). Co-treatment of Carvacrol
and cisplatin increased the survival rate of HeLa cells compared to
cisplatin treatment, and the MEK inhibitor decreased the viability of
HeLa cells (Potočnjak et al., 2018). Activation of ERK coincided with
decreased expression of mTOR and p-mTOR after Carvacrol treatment
(Potočnjak et al., 2018). In addition, in Carvacrol and cisplatin
cotreatment, the MEK inhibitor did not affect apoptosis but enhanced
autophagy in HeLa cell survival, suggesting autophagy as a cytotoxic
mechanism (Potočnjak et al., 2018). Table 3 and Fig. 3 shows the
7
Journal of Ethnopharmacology 314 (2023) 116575
autophagy regulators of polyphenols.
4.4. Terpenoids
4.4.1. Ursolic acid
Ursolic acid is a natural product found in Gladiolus italicus Mill.,
Freziera Sw. ex Willd., and other organisms. It has a variety of potential
pharmacological activities including anti-inflammatory, antioxidant,
antiviral, serum lipid-lowering, and antineoplastic activities (Sandhu
et al., 2023). After exposure to 30 μM of Ursolic acid for 24 h, there were
a large number of autophagic vacuoles were presented in TC-1 cells
(Leng et al., 2013). Meanwhile, TC-1 cells treated with Ursolic acid
showed accumulated vacuoles in the cytoplasm and punctate staining of
LC3, which was increased by Ursolic acid treatment in a
concentration-dependent manner (Leng et al., 2013). Gou et al. syn­
thesized an Ursolic acid derivative, UA232, and they found that UA232
activated protective autophagy in HeLa cells by increasing the
LC3II/LC3I ratio, promoting lysosomal biogenesis, and inducing lyso­
somal membrane permeabilization (Gou et al., 2022). These data sug­
gest that Ursolic acid may be a promising drug candidate for the
treatment of cervical cancer. Oleanolic acid is a natural product found in
Ophiopogon japonicus, Freziera, and other organisms. It is a structural
isomer of Ursolic acid (Panda et al., 2022). Treatment with Oleanolic
acid also increased cisplatin-induced LC3II and autophagy-related pro­
tein ATG5 expression (Potočnjak et al., 2019).
4.4.2. Hinokitiol
Hinokitiol is a natural product found in Chamaecyparis obtusa Siebold
& Zucc., Thujopsis dolabrata Siebold & Zucc., and other organisms. It has
a role as an antifungal agent, an antibacterial agent, an antiplasmodial
agent, an antineoplastic agent, and a plant metabolite (Chukwuma et al.,
2020). Hinokitiol suppresses the growth of lung cancer, breast cancer,
melanoma, and hepatocellular cancer cells by regulating cell death and
cell signaling pathways (Zhang et al., 2019). In HeLa cells, Hinokitiol
induced cellular senescence but not apoptosis as Hinokitiol treatment
did not induce caspase-3 activation and PARP cleavage (Wang C. C.
et al., 2020). It induced autophagy in HeLa cells as Beclin-1 and LC3II
were accumulated in a dose-dependent manner after the Hinokitiol
treatment (Wang C. C. et al., 2020). In cervical cancer cells, Hinokitiol
also inhibited the FAK, JNK, and p53/p21 pathways, resulting in the
decrease of cell proliferation and promotion of autophagy (Wang C. C.
et al., 2020).
T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

Table 4
Autophagy regulators of terpenoids.
Natural product Cell type Effect on Mechanism Reference
Autophagy

Ursolic acid TC-1 and HeLa Induction 1) increase in LC3II expression (Gou et al., 2022; Leng et al., 2013; Potočnjak et al.,
cells 2) translocation of lysosomes from the nucleus to the 2019)
plasma membrane
Hinokitiol HeLa cells Induction 1) inhibition of JNK and FAK phosphorylation Wang C. C. et al. (2020)
2) increase in LC3II expression
Astragaloside IV HeLa and SiHa Induction increase in LC3II expression Xia et al. (2020)
cells
Dihydroartemisinin HeLa cells Induction 1) increase in LC3II and Beclin-1 expressions (Tang et al., 2021; Wang L. et al., 2019)
2) increase in the formation of autophagosomes
3) increase in Bcl-2 phosphorylation
4) decrease in p-mTOR expression
Tubeimoside I HeLa and SiHa Induction 1) activation of AMPK Feng et al. (2018)
cells 2) stabilization of the Beclin1-Vps34 complex
3) accumulation of impaired autophagolysosomes
Triptolide SiHa cells Induction 1) increase in LC3II expression Qin et al. (2018)
2) decrease in p-Akt and p-mTOR expression
Glaucocalyxin B HeLa and SiHa Induction increase in LC3II expression Pan et al. (2016)
cells
Pulsatilla Saponin D HeLa cells Induction 1) increase in LC3II expression Zhang et al. (2015)
2) decrease in p-mTOR expression
Paclitaxel HeLa cells Induction increase in LC3II and Beclin-1 expressions (Peng et al., 2014; Wang et al., 2022; Xu et al., 2015;
Zou et al., 2018)

4.4.3. Astragaloside IV
Astragaloside IV is a natural product found in Euphorbia glareosa Pall.
ex M.Bieb., Astragalus ernestii H.F.Comber, and other organisms. It has a
role as a carbonic anhydrase inhibitor, an anti-inflammatory agent, a
neuroprotective agent, an antioxidant, a pro-angiogenic agent, and a
plant metabolite (Yao et al., 2023). Researchers have found that Astra­
galoside IV exerts anticancer effects by targeting PI3K/Akt/NF-κB,
Akt/GSK-3β/β-catenin, JNK/c-Jun/AP1, and other signaling pathways
(Wang et al., 2018). After 12 h of treatment with Astragaloside IV, cell
invasion was inhibited and LC3I/II was induced in SiHa and HeLa cells
(Xia et al., 2020). Using bioinformatics analysis, Xia et al. identified
differentially expressed proteins in Astragaloside IV-suppressed cervical
cancer cells and finally found that Astragaloside IV targeted DCP1A and
TMSB4X and induced autophagy, suppressing the proliferation and in­
vasion of cervical cancer cells (Xia et al., 2020).
4.4.4. Dihydroartemisinin
Dihydroartemisinin is a natural product found in Acronychia pubes­
cens C.T.White and other organisms. As an antimalarial drug, Dihy­
droartemisinin may be an effective anticancer chemotherapeutic agent
by regulating redox homeostasis (Moss et al., 2022). In HeLa cells,
Dihydroartemisinin significantly inhibited cell growth, and its inhibition
rate increased with the concentration of Dihydroartemisinin (Wang L.
et al., 2019). Meanwhile, the number of autophagosomes was elevated
after Dihydroartemisinin treatment, and the conversion of LC3I to LC3II
was also promoted (Wang L. et al., 2019). The study by Tang et al.’s
study also showed that the addition of Dihydroartemisinin resulted in
increased conversion of LC3I to LC3II in HeLa cells (Tang et al., 2021).
By blocking the autophagy pathway with 3-MA,
Dihydroartemisinin-induced cancer death was inhibited (Tang et al.,
2021).
4.4.5. Tubeimoside I
Tubeimosides are important pharmacologically active components
of the traditional Chinese medicine. Tubeimosides include four com­
pounds, including I, II, III, and V (Jia et al., 2015). Tubeimosides have
been reported to have a broad spectrum of anticancer activity against
gastric, liver, cervical, lung, ovarian, breast, colorectal, and esophageal
cancers (Islam et al., 2019). In cervical cancer, Tubeimoside I inhibited
cervical cancer cell proliferation both in vitro and in vivo (Feng et al.,
2018). It also induced autophagosome formation in HeLa and SiHa cells
as both the endogenous LC3 and exogenous GFP-LC3 puncta were
significantly increased in Tubeimoside I-treated cells (Feng et al., 2018).
Mechanically, Tubeimoside I initiated autophagy by activating AMPK
and stabilizing the Beclin1-Vps34 complex, resulting in the accumula­
tion of impaired autophagolysosomes (Feng et al., 2018).
4.4.6. Triptolide
Triptolide is a natural product found in Tripterygium hypoglaucum
Hutch., Celastraceae R.Br., and other organisms. Triptolide has been
used in studies investigating the treatment of HIV, Crohn’s disease, in­
testinal diseases, gastrointestinal diseases, and diseases of the digestive
system (Sun R. et al., 2022). Triptolide treatment significantly inhibited
the viability of SiHa cells in a dose- and time-dependent manner (Qin
et al., 2018). It increased LC3 protein expression in SiHa cells and sup­
pressed the expression of p-mTOR, p-Akt, and p-p70S6K proteins (Qin
et al., 2018). In human prostate cancer cells, Zhao et al. also reported
that Triptolide induced autophagy by suppressing the expression of
mTOR (Zhao et al., 2016). These data indicated that Triptolide induced
autophagy through the PI3K/Akt/mTOR/p70S6K-associated pathway.
4.4.7. Glaucocalyxin B
Glaucocalyxin B is a natural product found in Isodon pharicus (Prain)
Murata and Isodon japonicus (Burm.f.) H.Hara. It has been reported that
cervical cancer, ovarian cancer, and gastric cancer could be inhibited by
Glaucocalyxin B (Zhang T. et al., 2022). Glaucocalyxin B and cisplatin
synergized to induce cell death in human ovarian cancer cells (Zhang T.
et al., 2022). In cervical cancer, Glaucocalyxin B could inhibit the pro­
liferation of SiHa and HeLa cells, and it increased LC3II/I protein
cleavage in both cell lines (Pan et al., 2016). In addition, Glaucocalyxin
B increased the PTEN expression and decreased p-AktS473 expression,
while the total Akt remained unchanged by Glaucocalyxin B treatment
(Pan et al., 2016). These results suggest that the antitumor activity of
Glaucocalyxin B is related to the PI3K/Akt signaling pathway.
4.4.8. Pulsatilla saponin D
Pulsatilla saponin D is a natural product found in Anemone coronaria
L., Serjania salzmanniana Schltdl., and Hedera colchica (K.Koch) K.Koch.
It has anticancer effects on a wide range of cancers, including gastric
cancer, colon cancer, hepatocellular carcinoma, and pancreatic cancer
(Fang et al., 2019). Treatment with Pulsatilla saponin D exhibited potent
cytotoxicity against HeLa cells in a time- and dose-dependent manner
(Zhang et al., 2015). Meanwhile, Pulsatilla saponin D induced a time-
and dose-dependent accumulation of LC3II and p62 in HeLa cells, and

8
T. Tao et al.
Fig. 4. The autophagy regulators of terpenoids.
the co-treatment with Pulsatilla saponin D and an autophagic flux in­
hibitor did not change LC3II level (Zhang et al., 2015). These results
strongly suggested that Pulsatilla saponin D could inhibit
autophagy-lysosomal degradation.
4.4.9. Paclitaxel
Paclitaxel is a tetracyclic diterpenoid originally isolated from the
bark of the Pacific yew tree, Taxus brevifolia Nutt. It is a mitotic inhibitor
used in cancer chemotherapy (Della Corte et al., 2020). Although
Paclitaxel is a potent inhibitor of chromosome replication, acquired
chemoresistance limits the successful treatment of cervical cancer
(Gennigens et al., 2022). In the study conducted by Peng et al., increased
autophagy was observed in Paclitaxel-resistant HeLa cells, and
9
Journal of Ethnopharmacology 314 (2023) 116575
3-methyladenine or ATG7 small interfering RNA restored the sensi­
tivity of resistant HeLa cells to Paclitaxel (Peng et al., 2014). Paclitaxel
also induced the aggregation of autophagosomes in the cytoplasm of
HeLa cells, and Beclin-1 and LC3II expressions were increased, and p62
expression was decreased, suggesting that Paclitaxel promotes auto­
phagy (Xu et al., 2015). Zou et al. found that Paclitaxel inhibited cervical
cancer progression by inducing autophagy, which could be reversed by
the long non-coding RNA RP11-381N20.2 (Zou et al., 2018). In addition,
the sensitivity of cervical cancer cells to Paclitaxel could be increased by
overexpression of aplysia ras homolog I as the protective autophagy was
induced (Wang et al., 2022). Table 4 and Fig. 4 shows the autophagy
regulators of terpenoids.
T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

Table 5
Autophagy regulators of quinones.
Natural Cell Effect on Mechanism Reference
product type Autophagy

Physcion HeLa Induction increase in LC3 Trybus et al.

cells expression (2021)
Chrysophanol HeLa Induction 1) increase in Trybus et al.
cells lysosomes (2021)
and
autophagic
vacuoles
2) digestion of a
large portion
of the
cytoplasm
with
organelle
Plumbagin SiHa Induction increase in LC3II Periasamy et al.
cells expression (2022)
Emodin HeLa, Induction Increase in the (Galiardi-Campoy
SiHa, number of et al., 2021;
CaSki, lysosomes and Trybus et al.,
and autophagic 2017)
HaCaT vacuoles
cells

4.5. Quinones

4.5.1. Physcion
Physcion is a natural product found in Rumex dentatus L., Ageratina
altissima (L.) R.M.King & H.Rob., and other organisms. It has a role as a
metabolite, an antibacterial agent,an apoptosis inducer, a hep­
atoprotective agent, an antineoplastic agent, an antifungal agent, and an
anti-inflammatory agent (Wang et al., 2021). Physcion is cytotoxic to
human cervical carcinoma HeLa cells (Wijesekara et al., 2014). At a
concentration of 80 μM, an increase in the number of vacuoles in the
cytoplasm was shown in Physcion-treated HeLa cells (Trybus et al.,
2021). After 48 h of Physcion treatment, HeLa cells showed a significant
elevation in the number of autophagic LC3-positive cells (Trybus et al.,
2021). The results obtained suggest that Physcion may find future ap­
plications in cervical cancer therapy.
4.5.2. Chrysophanol
Chrysophanol is a natural product found in Rumex dentatus L.,
Ageratina altissima (L.) R.M.King & H.Rob., and other organisms. It has
been isolated from Aloe vera and shows antiviral and anti-inflammatory
activity (Alves et al., 2020). In the in vitro experiments, Chrysophanol
showed promising anticancer activity in HeLa cells (Ahmad et al., 2022).
Chrysophanol could promote DNA damage and the concentrations of
160 and 300 μM could result in a gradual intensification of DNA breaks
(Trybus et al., 2021). Chrysophanol could also induce autophagy, and at
a 80 μM of Chrysophanol, small vacuoles was shown in HeLa cells
(Trybus et al., 2021). Increased autophagy was observed at concentra­
tions of 200 μM and 300 μM (Trybus et al., 2021).
4.5.3. Plumbagin
Plumbagin is a secondary metabolite found in the roots of plants
belonging to Plumbaginaceae Juss., Ebenaceae Gürke, and Droseraceae
Salisb. Plumbagin is a compound that has been studied for its anticancer
activity (Ortiz-Pérez et al., 2021). It has been found to inactivate the
Akt/NF-kB, MMP-9, and VEGF pathways (Yin et al., 2020). In cervical
cancer, Plumbagin downregulated UHRF1, p-Akt, and MMP-2 and sup­
pressed survival, growth, and migration of CaSki cells (Sidhu and
Capalash, 2023). Plumbagin could induce DNA damage, and it triggered
DNA fragmentation in SiHa cells, showing comet-like structure forma­
tion by migration of DNA fragments from the nuclei (Periasamy et al.,
2022). In SiHa cells, Plumbagin could promote autophagic cell death,
and it could accumulate LC3-positive autophagosomes in
Fig. 5. The autophagy regulators of quinones.
Plumbagin-treated SiHa cells (Periasamy et al., 2022).
4.5.4. Emodin
Emodin is a natural product found in Rumex dentatus L., Rhamnus
davurica Pall., and other organisms. It has a role as a plant metabolite, a
laxative, an antineoplastic agent, and a tyrosine kinase inhibitor
(HaoShang et al., 2023). In the in vitro experiments, Emodin showed
promising anticancer activity in HeLa cells (Ahmad et al., 2022).
Meanwhile, Emodin increased the number of damaged spindles, cells
with abnormal mitosis, cells with micronuclei, giant cells, and poly­
morphonuclear cells (Trybus et al., 2019). Emodin changed the lyso­
somal compartment, manifested by an increase in the activity of
lysosomal hydrolases and the number of autophagic vacuoles and ly­
sosomes (Trybus et al., 2017). In addition, a decrease in cell viability
was observed in HaCaT, CaSki, and SiHa cells after Emodin treatment
combined with photodynamic therapy, and such effects were exerted by
ROS production, leading to cell death by inducing apoptosis and auto­
phagy (Galiardi-Campoy et al., 2021). Table 5 and Fig. 5 shows the
autophagy regulators of quinones.
4.6. Others
4.6.1. Saponins——RCE-4 and ginsenoside
RCE-4 is a saponin isolated from the traditional Chinese herb Mam­
millaria carnea Zucc. ex Pfeiff. RCE-4 has been used to treat diseases such
as hepatitis, cough, and rheumatism (Zheng et al., 2021). RCE-4 was
found to induce autophagy in CaSki cells as evidenced by an increase in
the formation of autophagosomes following treatment with RCE-4
(Xiang et al., 2020). However, Beclin-1 expression was not upregu­
lated in the RCE-4-treated cells (Xiang et al., 2020). With prolonged
treatment time, RCE-4 impaired lysosomal cathepsin activity and
inhibited autophagy flux by suppressing the expression of p-Beclin-1,
p-ULK1, and p-AMPK, and upregulating p62 (Xiang et al., 2020).
Meanwhile, RCE-4 inhibited the formation of the Bcl-2-Beclin-1 complex
in CaSki cells through multiple pathways, and ATG4B proteins involved

10
T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

in this process served as a key cofactor (You et al., 2021). Table 6

Ginsenoside is a natural product found in Panax ginseng C.A.Mey. and Autophagy regulators of other natural products.
Panax notoginseng (Burkill) F.H.Chen ex C.Y.Wu & K.M.Feng. It has a Natural product Cell Effect on Mechanism Reference
role as a plant metabolite, an antineoplastic agent, an apoptosis inducer, type Autophagy
a cardioprotective agent, a bone density maintaining agent (Feng et al., RCE-4 CaSki Induction 1) increase in the (Xiang et al.,
2022). Total ginsenoside induced autophagy in cervical cancer cells in a cells formation of 2020; You
time- and concentration-dependent manner as an increase in the pro­ autophagosomes et al., 2021)
cessing of LC3I to LC3II (Bian et al., 2021). Ginsenoside also significantly 2) increase in
ULK1, p-ULK1,
promoted the expression of Beclin-1, ATG5, and downstream LC3II at p-Beclin-1, and
the protein level, and down-regulated the level of p62 (Yin et al., 2021). LC3II
There is increasing evidence that Ginsenoside Rh2 exerts antitumor ef­ expressions
fects in various cancer models (Shi et al., 2016; Wang et al., 2017). 3) dual blockade of
ERK and PI3K
Ginsenoside Rh2 increased the number of LC3II puncta in normal and
pathways
starved HeLa and C-33A cells, and the accumulation of autophagic 4) inhibition of
vacuoles was increased in Ginsenoside Rh2-treated cells (Wang J. et al., formation of the
2020). The study by Bian et al. showed that Ginsenoside Rh2-induced Bcl-2-Beclin-1
protective autophagy promoted apoptosis of cervical cancer cells by complex
Ginsenoside HeLa, Induction 1) inhibition of (Bian et al.,
inhibiting the AMPK/mTOR pathway (Bian et al., 2021). MS751, AMPK-mTOR 2021; Bian
and C- signaling et al., 2021;
4.6.2. Lactones——Alantolactone and parthenolide 33A pathway Wang J.
Alantolactone is a natural product found in Eupatorium cannabinum cells 2) increase in LC3II et al., 2020;
and Beclin-1 Yin et al.,
L., Hieracium britannicum F.Hanb., and other organisms. It has a role as a
expressions 2021)
plant metabolite, an apoptosis inducer, and an antineoplastic agent (Cai Alantolactone HeLa Induction increase in LC3II Sun et al.
et al., 2021). Treatment of HeLa cells with alantolactone for 12 h and and Beclin-1 (2021)
significantly inhibited growth in a dose-dependent manner, and it SiHa expressions
induced apoptosis of HeLa cells via generation of reactive oxygen spe­ cells
Parthenolide HeLa Induction 1) increase in Jeyamohan
cies, glutathione depletion, and inhibition of the Bcl-2/Bax signaling
cells Beclin-1 et al. (2016)
pathway (Jiang et al., 2016). The cell experiment of HeLa and SiHa cells expression
showed that the autophagosomes were increased (Sun et al., 2021). The 2) decrease in
xenograft model of HeLa cells showed that the protein levels of Beclin-1 mTOR, PI3K,
and Akt
and LC3B were increased, while the protein level of p62 was decreased
expressions
in the tumor tissues (Sun et al., 2021). Syringin HeLa Induction increase in LC3II Sun S. et al.
Parthenolide is a natural product found in Cyathocline purpurea cells expression (2022)
Kuntze, Tanacetum parthenium Sch.Bip., and other organisms. It has roles HTF-1 HeLa Induction increase in LC3II (Ma et al.,
as a drug allergen, an inhibitor, a peripheral nervous system drug, a non- cells expression 2018; Man
et al., 2019)
narcotic analgesic, and a non-steroidal anti-inflammatory drug (Liu and
Crocin SiHa Induction 1) increase in LC3II Zhang et al.
Wang, 2022). Parthenolide inhibited the growth of SiHa cells in a cells and Beclin-1 (2020)
concentration-dependent manner at 24- and 48-h time intervals expressions
(Al-Fatlawi et al., 2015). In the study by Jeyamohan et al., most of the 2) inhibition of
AMPK and
HeLa cells treated with Parthenolide showed damaged DNA and frag­
mTOR signaling
mented nuclei (Jeyamohan et al., 2016). Meanwhile, ATG3 was upre­ Fucoxanthin HeLa Induction 1) increase in LC3II Hou et al.
gulated and p-Akt was downregulated in Parthenolide-treated cells, cells and Beclin-1 (2013)
suggesting that Parthenolide inhibits the PI3K/Akt signaling pathway expressions
and thus induces autophagy in HeLa cells (Jeyamohan et al., 2016). 2) decrease in p-
Akt and p-mTOR
expressions
4.6.3. Glycosides——Syringin and HTF-1 Angelicin HeLa Induction 1) increase in LC3II Wang Y.
Syringin, also known as Eleutheroside B, is a natural product found and expression et al. (2019)
in Salacia chinensis L., Codonopsis lanceolata (Siebold & Zucc.) Benth. & SiHa 2) increase in
cells mTOR
Hook.f. ex Trautv., and other organisms. It has a role as a hep­
phosphorylation
atoprotective agent and a plant metabolite (Li et al., 2016). Studies have Glucocappasalin HeLa Induction 1) inhibition of Xu et al.
shown that Syringin has been proven to be cytotoxic to human breast cells PI3K/Akt (2021)
cancer cells, prostate cancer cells, and glioblastoma. In cervical cancer, signaling
Syringin significantly decreased the expression of LC3I and increased pathway
2) increase in LC3II
the expression of LC3II in HeLa cells (Sun S. et al., 2022). In addition,
and Beclin-1
HeLa cells treated with Syringin decreased p62 protein levels in a expressions
concentration-dependent manner, suggesting that Syringin could induce Concanavalin A HeLa Induction 1) inhibition of Roy et al.
autophagy in HeLa cells (Sun S. et al., 2022). cells PI3K/Akt/mTOR (2014)
HTF-1 is a kind of cardiac glycoside that is isolated from the roots signaling
pathway
and rhizomes of Helleborus thibetanus Franch. HTF-1 induced apoptosis 2) activation of
against several types of cancer cells in a concentration- and time- MEK/ERK
dependent manner, and it can inhibit cancer cells in proliferation, in­ signaling
vasion, and migration (Ma et al., 2018). In addition, HTF-1 activates pathway
Sesamin HeLa Induction increase in LC3II Dou et al.
JNK but suppresses ERK and PI3K-Akt-mTOR signaling pathways (Ma
cells and Beclin-1 (2018)
et al., 2018). In cervical cancer, HTF-1 induced ROS-independent expressions
autophagy as the abundance of LC3II was increased and showed a (continued on next page)
dose-dependent manner (Man et al., 2019). HTF-1-induced autophagy

11
T. Tao et al. Journal of Ethnopharmacology 314 (2023) 116575

Table 6 (continued ) 2019). Glucocappasalin is a natural product derived from the seeds of
Natural product Cell Effect on Mechanism Reference Descurainia sophia (L.) Webb ex Prantl, and it induced cell cycle
type Autophagy G2/M-phase arrest, apoptosis, and, autophagy by acting on the
Punicalagin HeLa Induction 1) decrease in E6 Xie et al.
PI3K/AKT/mTOR signaling pathway (Xu et al., 2021). Concanavalin A is
cells and E7 (2022) a mannose-binding lectin originally isolated from jack-bean, and Can­
expressions avalia ensiformis (L.) DC., and it suppressed the PI3K/Akt/mTOR and
2) increase in LC3II upregulated the MEK/ERK pathway, leading to the activation of auto­
expression
phagy in HeLa cells (Roy et al., 2014). Sesamin is a natural product
3) activation of
ROS-JNK-BCL2 found in Pandanus boninensis Warb., Podolepis rugata Labill., and other
pathway organisms, and it activates autophagy and autophagic death in HeLa
cells via increasing LC3II and Beclin-1 expression (Dou et al., 2018).
Punicalagin is a polyphenolic tannin derived from the pomegranate, and
partially contributed to its anticancer activity against HeLa cells (Man it significantly reduced the levels of E6 and E7 through the
et al., 2019). autophagy-lysosome system (Xie et al., 2022). In addition,
Punicalagin-induced degradation of E6 and E7 in HeLa cells was
4.6.4. Other natural products dependent on autophagy (Xie et al., 2022). Table 6 and Fig. 6 shows the
In addition to the natural products mentioned above, many other autophagy regulators of other natural products.
compounds have been identified to play a critical role in autophagic
regulation in cervical cancer. Crocin is a natural product found in 5. Clinical trials
Gardenia jasminoides J.Ellis, Calycanthus L., and other organisms, and it
induced autophagic cell death and inhibited cell invasion of SiHa cells Some of the natural products mentioned above have been used in
by activating the PI3K/AKT signaling pathway (Zhang et al., 2020). clinical trials. In a randomized controlled trial, radiation-induced acute
Fucoxanthin is a natural product found in Aequipecten opercularis, Asci­ intestinal symptoms were reduced after oral administration of Berberine
dia zara, and other organisms, and it increased the protein expression of in 21 cervical cancer patients undergoing radiation therapy (Li et al.,
LC3II and Beclin-1in HeLa cells (Hou et al., 2013). In addition, Fuco­ 2010). In a prospective phase I study, the oral administration of Cur­
xanthin dose-dependently decreased the levels of phosphorylated Akt cumin in patients with cervical intraepithelial neoplasm (CIN) improved
and its downstream proteins p53, p70S6K, and mTOR, and increased the histologic outcomes (1 of 4), and 1 of 4 patients progressed to overt
expression of PTEN in HeLa cells (Hou et al., 2013). Angelicin is a nat­ malignancy despite curcumin treatment (Cheng et al., 2001). In a phase
ural product found in Cullen cinereum (Lindl.) J.W.Grimes, Psoralea II study called PRIMMO (identifier NCT03192059), patients with cer­
glabra E.Mey., and other organisms, and it inhibited the malignant vical cancer received an immunomodulatory five-drug cocktail (IDC)
behavior of HeLa and SiHa cells, possibly by inhibiting autophagy, as it consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin
caused the accumulation of LC3B in the cytoplasm (Wang Y. et al., D, and Curcumin starting 2 weeks prior to radioimmunotherapy.

Fig. 6. The autophagy regulators of other natural products.

12
T. Tao et al.
However, PRIMMO did not meet its primary objective in either cohort;
IDC had modest but durable antitumor activity with acceptable but not
negligible toxicity (De Jaeghere et al., 2023). The first study of oral
Dihydroartemisinin in advanced cervical cancer showed that Dihy­
droartemisinin improved clinical symptoms and was well tolerated in
patients with advanced cervical cancer (Jansen et al., 2011).
With the widespread adoption of cisplatin-based chemoradiation
protocols for locally advanced cervical cancer, acquired platinum
resistance at relapse became a concern. A phase II trial of topotecan-
paclitaxel demonstrated activity in a pre-irradiated population of
women with recurrent cervical cancer (Tiersten et al., 2004). However, a
recent clinical trial showed that topotecan plus paclitaxel did not confer
a survival benefit in women with recurrent/metastatic cervical cancer,
even in platinum-exposed patients (Tewari et al., 2023). Compared to
paclitaxel, nanoparticle albumin-bound paclitaxel has improved uptake
by tumor cells, and complete responses have been observed in 20 of 22
patients with mild side effects (Jiang et al., 2023). Therefore, the effi­
cacy of paclitaxel in patients with cervical cancer needs to be further
investigated.
6. Conclusion and perspective
The regulation of cervical cancer autophagy by natural products has
significant advantages in inducing apoptosis, inhibiting proliferation,
and reducing drug resistance in cervical cancer. This review revealed
that the regulation of cervical cancer cell autophagy by natural products
has two effects: activation of early-stage autophagy can promote cell
apoptosis by increasing lysosomal membrane permeability, enhancing
chemotherapeutic drug sensitivity, and activating autophagic flux
through multiple pathways such as PI3K/Akt/mTOR, AMPK, and ROS;
or in advanced stages of autophagy by promoting autophagosome for­
mation. Although most natural products have an inducible function to
autophagy, some natural products can inhibit autophagy in the late
stages. In addition, the activation of autophagy in the early stage and
inhibition in the late stage may increase the sensitivity of chemothera­
peutic drugs and reverse multidrug resistance, the specific mechanism of
which needs to be further investigated.
In vitro experiments on autophagy modulation by natural products
have achieved certain effects, but clinical experimental studies are
scarce and lack a reliable clinical theoretical basis. Therefore, it is
essential to conduct more clinical experimental studies on autophagy
modulation by natural products to seek a more reliable theoretical basis
for the treatment of cervical cancer.
Funding
None.
CRediT authorship contribution statement
Tao Tao: Writing – original draft. Ping Zhang: Writing – review &
editing. Zhi Zeng: Writing – review & editing. Min Wang: Conceptu­
alization. Zhi Zeng: Writing – review & editing. Min Wang:
Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
13
Journal of Ethnopharmacology 314 (2023) 116575
Acknowledgments
None.
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