Natural autophagy regulators in cancer therapy: a review

Qian Ding • Jiaolin Bao • Wenwen Zhao •

Yangyang Hu • Jinjian Lu • Xiuping Chen

Received: 4 September 2013 / Accepted: 12 February 2014

� Springer Science+Business Media Dordrecht 2014

Abstract Autophagy is a complicated self-eating

response of cells to external or internal stimuli. This

process involves cellular degradation through the

lysosomes of dysfunctional or unnecessary cellular

components or organelles to maintain basic energy

levels. This nonapoptotic programmed cell death,

similar to other main phenomena of cell biology such

as apoptosis and differentiation, has been implicated in

the pathogenesis of a series of disorders, such as

neurodegenerative diseases, cardiovascular diseases,

and especially in cancer. Increasing evidence has

suggested that the autophagy pathways may provide

potential targets for cancer intervention, although their

precise roles in cancer initiation and progression

remain controversial. Natural products are very

important sources of chemotherapeutics agents. Reg-

ulation of autophagy could be an important mecha-

nism contributing to the beneficial effect of quite a few

natural products. Herein, we briefly introduce the

characteristics and roles of autophagy in cancer and

systematically summarize the natural autophagy reg-

ulators, with emphasis on apigenin, berberine, beta-

elemene, capsaicin, curcumin, genistein, kaempferol,

oridonin, paclitaxel, quercetin, resveratrol, silybin,

triptolide, and ursolic acid, with the aim to provide

information for novel avenues on cancer therapies

based on autophagy.

Keywords Autophagy � Cancer � Natural

products � Drug discovery

Introduction

Autophagy, the recently intensive attracted form of

cell death, means ‘‘self-eating’’ derived from the

Greek words (auto ‘‘self’’ ? phagein ‘‘to eat’’). It is a

complicated cellular process involved in protein and

organelle degradation. When cells encounter certain

stresses and drug insults such as starvation or some

chemotherapeutics, they are forced to break down

parts of their own cellular components to supply

amino acids and energy for survival. During this

process, the cytoplasmic constituents together with the

isolated membrane are separated from the rest of the

cell to form autophagosomes. These autophagosomes

are then fused with lysosomes to form the autolyso-

some for further degradation or recycling. The basal

levels of autophagy are considered to play an impor-

tant role in maintaining normal cellular homeostasis

while excessive autophagy has been found to be

associated with the pathogenesis of a series of

diseases, such as cancer, neurodegeneration, microbial

infection, aging, and so on (Mizushima et al. 2008).

Q. Ding � J. Bao � W. Zhao � Y. Hu � J. Lu �X. Chen (&)

State Key Laboratory of Quality Research in Chinese

Medicine, Institute of Chinese Medical Sciences,

University of Macau, Av. Padre Tomas Pereira S.J.,

Taipa, Macau, China

e-mail: chenxiu0725@yeah.net; xpchen@umac.mo

123

Phytochem Rev

DOI 10.1007/s11101-014-9339-3

The central regulator of the autophagy pathway in

mammalian cells is the mammalian target of rapamy-

cin (mTOR), a potent negative regulator. Numerous

signaling pathways converge in mTOR, which forms

two complexes in mammalian cells: mTOR complex1

(mTORC1) and mTOR complex2 (mTORC2). Of

these two complexes, only mTORC1 is sensitive to

rapamycin which is widely used as a canonical

allosteric inhibitor of mTOR and autophagy inducer.

mTORC1 is also claimed to be the sensor of cellular

nutrient status (Shintani and Klionsky 2004). The

activation of AMP-activated protein kinase (AMPK),

one of the central regulators in cellular metabolism,

phosphorylates and inhibits mTORC1 (Gleason et al.

2007). P53, the pleiotropic tumor suppressor, has a

dual function in the regulation of autophagy. On the

one hand, nuclear P53 can induce autophagy through

transcriptional effects. On the other hand, cytoplasmic

P53 may act as a master repressor of autophagy

(Maiuri et al. 2009). The mTOR pathway can also be

regulated by the mitogen-activated protein kinase

(MAPK) subfamily in autophagy (Tang et al. 2008;

Wu et al. 2011). Class I PI3K (PI3KI) signaling

through Akt serves to inhibit autophagy by activating

mTORC1, whereas mTORC2 may phosphorylate and

activate Akt at S473 (Baek et al. 2012). Therefore,

these two pathways converge in the upstream of

mTORC1. The tuberous sclerosis complex (TSC)

complex TSC1/TSC2 suppresses mTORC1 by deac-

tivating Ras homolog enriched in brain (Rheb), the

mTORC1-interacting protein (Wang et al. 2011b).

The mTOR represses autophagy by regulating the

ULK1 kinase complex, which consist of the serine-

threonine kinase ULK1, Atg13, and FIP200 (Tooze

et al. 2010). The phosphorylated and stabled complex

of ULK1, Atg13 and FIP200 located on the phago-

phore is able to induce autophagy. The class III PI3K

complex, including Beclin 1 (the mammalian homolog

of yeast Atg6), serves to recruit other constituent

proteins to the autophagosomal membrane after

autophagy induction (Dong et al. 2010). Subsequent

mediators of autophagy include autophagy-related

(Atg) proteins (such as Atg12, Atg5, Atg7, Atg3,

Atg10, Atg16L), microtubule-associated protein light

chain 3 (LC3), lysosomal-associated proteins 1 and 2

(LAMP1 and LAMP2) and among others. Atg12, the

first modifier essential to the formation of autophag-

osomal precursors, is activated by Atg7 and trans-

ferred to Atg10, and finally is conjugated to Atg5. The

Atg12–Atg5 conjugates further forms a *350 kDa

multimeric complex with Atg16 (Hanada et al. 2007).

LC3, the second modifier essential for the later

formation of autophagosomes, is immediately pro-

cessed by Atg4 into LC3-I after synthesis. During

autophagosome formation, LC3-I is incorporated into

autophagosome membranes mediated by Atg3 and

Atg7. This results in the conversion of cytosolic LC3-I

into the active, autophagosome membrane-bound

form, LC3-II. Thus, the expression ratio of LC3-I to

LC3-II provides a simple indicator for autophagy

activity in mammals (Tanida et al. 2004). P62, an

ubiquitin binding protein, acts as a scaffolding/adaptor

protein that binds to LC3 in autophagy. After

autophagosome formation, LAMP1 and LAMP2 are

fused with it to form autolysosomes (Corcelle et al.

2009). The final phase, which is the breakdown of the

autophagic bodies and their contents, yields the

recycled substrates required by the nutrient-deprived

cells for protein synthesis and ATP generation (Dong

et al. 2010) (Fig. 1).

Although apoptosis is the primary form of chemo-

therapy induced cell death, the autophagic cell death

has emerged as another important mechanism of

cancer cell death induced by anti-cancer drugs.

However, autophagy may also serve as a pro-survival

mechanism at the early stage of cancer treatment by

eliminating dysfunctional organelles to maintain can-

cer cells’ basical energy levels, therefore protecting

cancer cells that are being attacked by chemotherapies

from undergoing death. The roles that autophagy play

in cancer, either via a cell survival mechanism or a cell

death induction, may be cancer-type specific, and may

be influenced by the genetic makeup of the corre-

sponding cancer cells and the nature of the external

stresses to which they are exposed (Bialik and Kimchi

2008). Nonetheless, the mainstream research holds an

optimistic view of promising drug discoveries by

modulating autophagy for future cancer therapy

(Cheong et al. 2012; Janku et al. 2011).

Autophagy regulators from natural products

Natural products are very important sources of

chemotherapy for cancer and quite a few of them,

such as vinblastine, etoposide, and camptothecin, have

been added to the repertoire of chemotherapeutics.

Although most anti-cancer drugs hit different targets,

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their common final effect is cell-killing mainly by

induction of apoptosis. However, recent evidence

demonstrates that some of these agents are also potent

autophagy regulators (mainly autophagy inducer),

suggesting the active role of autophagy modulation

in their overall therapeutic effects. In view of the

important role of natural products in modern drug

discovery and the rapid identification of them as

potential autophagy regulators, herein, we have sum-

marized the latest research results on this issue.

Apigenin

Apigenin, a member of the flavone subclass of

flavonoids widely presented in fruits and vegetables,

has been used to treat asthma, intransigent insomnia.

Its role in cancer chemoprevention has also been well

recognized (Liu et al. 2005; Patel et al. 2007). Some

studies show that apigenin inhibits human cancer cell

growth via the promotion of cell cycle arrest and

apoptosis in cervical, colon, ovarian cancer and

leukemia (Elsisi et al. 2005; Gupta et al. 2002).

Gordon et al. (1995) firstly reported that apigenin

could reverse okadaic acid-induced strong inhibitory

effect on autophagy in isolated rat hepatocytes.

Subsequently, it was reported that apigenin initiated

autophagy without inducing apoptosis in TF1

erythroleukemia cells (Ruela-de-Sousa et al. 2010).

Apigenin inhibited the proliferation of T47D and

MDA-MB-231 breast cancer cells by inducing apop-

tosis. Simultaneously, autophagy was induced and the

inhibition of autophagy by 3-MA enhanced the

apoptosis (Cao et al. 2013). This suggested the cyto-

protective role of autophagy in these cells. Further-

more, apigenin worked synergistically with retinoid

N-(4-hydroxyphenyl) retinamide to suppress starva-

tion-induced autophagy and promoted apoptosis in

human malignant neuroblastoma cells (Mohan et al.

2011).

Berberine

Berberine is an isoquinoline alkaloid widely distrib-

uted in plants of Berberis and Coptis. It has a wide

range of pharmacologic effects, including anti-cancer

activities by induction of cell death, suppression of

tumor growth and metastasis (Sun et al. 2009). In

HepG2 and MHCC97-L cells, berberine induces both

mitochondrial apoptosis and autophagic cell death.

Autophagy is mediated by activation of Beclin-1 and

inhibition of the mTOR-signaling pathway, which is

suppressed by activity of Akt and up-regulating p38

MAPK signaling (Wang et al. 2010). Berberine-

induced apoptosis and autophagy in HepG2 and

Fig. 1 Cancer-associated autophagy signaling pathways in

mammalian cells. mTORC1 is the key regulator of the

autophagy pathway. Several signaling pathways converge in

mTORC1, including AMPK, AKT, MAPK/Erk1/2 and P53

signaling. mTORC1 inhibition activates the downstream ULK1

kinase complex, thus inducing autophagy. Class III PI3K

complex serves to recruit other constituent proteins to the

autophagosomal membrane. Atg12 is the first modifier essential

to the formation of autophagosomal precursors and isolation

membranes. LC3 is the second modifier essential to the later

formation of autophagosomes

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SMMC7721 is markedly reduced by overexpression

of CD147, a cellular adhesion molecule highly

expressed on the surface of various malignant tumor

cells. Thus, downregulation of CD147 might be a new

mechanism of berberine-induced cell death (Hou et al.

2011). However, in normal cells, autophagy induced

by berberine serves as cyto-protective. Berberine

alleviates cisplatin-induced renal injury by inhibiting

oxidative/nitrosative stress, autophagy and apoptosis

(Domitrovic et al. 2013).

Beta-elemene

Elemene, a class of lipid-soluble sesquiterpenoids

extracted from the essential oil of Rhizoma zedoariae,

has been approved by the SFDA as an anti-cancer

drug. Several types of elemene exist, such as a-

elemene, b-elemene, and c-elemene. b-elemene, the

most active type, has been shown to be effective

against various cancer, such as lung and colorectal

cancer, and glioblastoma (Lu et al. 2012). b-elemene

inhibits the proliferation of human renal-cell carci-

noma 786-0 cells by inducing apoptosis, as well as

protective autophagy. The anti-cancer effect is asso-

ciated with the inhibition of MAPK/ERK and PI3K/

Akt/mTOR signaling pathways (Zhan et al. 2012). It

also inhibits the activity of the PI3K/Akt/mTOR/

p70S6K1 signaling pathway in human lung cancer

A549 cells, human gastric cancer MGC803 and

SGC7901 cells, which also results in apoptosis as

well as protective autophagy (Liu et al. 2011, 2012a).

13,14-bis (cis-3,5-dimethyl-1-piperazinyl)-b-elem-

ene, a b-elemene derivative, demonstrates potent

anti-cancer activities by the inhibition of mTOR and

the induction of autophagy in human breast cancer

cells (Ding et al. 2013).

Capsaicin

Capsaicin, the major pungent component in hot red

peppers of the genus capsicum, is usually served as a

food additive. Though conflicting epidemiologic data

and basic research results reveal that capsaicin

possesses both carcinogenic and anticarcinogenic

potentials, it is widely postulated as a chemopreven-

tative (Bley et al. 2012; Bode and Dong 2011). Beside

apoptosis, capsaicin induces autophagic cell death and

endoplasmic reticulum (ER) stress in MCF-7 and

MDA-MB-231 cells. Autophagy blockage by 3-MA or

bafilomycin A1 activates caspase-4 and -7 and

enhances cell death. Furthermore, capsaicin-induced

autophagy is regulated by p38 MAPK and ERK, which

play key roles at the sequestration and the maturation

step of autophagy respectively. Capsaicin-induced

autophagy retards apoptotic cell death mediated by ER

stress in these cells (Choi et al. 2010a). Herein, this

suggests that autophagy serves as a pro-survival

mechanism. While dihydrocapsaicin, a saturated

structural analog of capsaicin, activates autophagy in

HCT116, MCF-7, and WI38 cells in a P53-indepen-

dent manner, which contributes to its cytotoxicity (Oh

et al. 2008).

Curcumin

Curcumin, a natural polyphenol derived from the

rhizome of Curcuma longa, is commonly used as a

flavoring agent in food and has been proved to be a

potent anti-cancer agent in a large number of studies.

Curcumin restricts tumor cell growth both in vitro and

in vivo by cell cycle arrest and apoptosis induction

(Reuter et al. 2008). Recent evidence reveals that

curcumin is a potent autophagy inducer in quite a few

human cancer cell lines in vitro, such as malignant

glioma U87-MG and U373-MG cells (Aoki et al.

2007); oesophageal squamous and adenocarcinoma

cell lines OE21, OE33 and KYSE450 cells (O’Sulli-

van-Coyne et al. 2009); erythromyeloblastoid leuke-

mia K562 cells (Jia et al. 2009); mesothelioma cell line

ACC-MESO-1 (Yamauchi et al. 2012); colon cancer

cells HCT116 (Lee et al. 2011); uterine LMS cell

lines: SKN and SK-UT-1 (Liu et al. 2013b); oral

squamous cell carcinoma cells YD10B (Kim et al.

2012a). It also enhances adriamycin-induced HepG2

cell death through activation of mitochondria-medi-

ated apoptosis and autophagy (Qian et al. 2011).

Curcumin-induced nonapoptotic autophagic cell death

is mediated by a simultaneous inhibition of the Akt/

mTOR/p70S6K1 pathway and stimulation of the ERK

pathway in U87-MG and U373-MG cells (Aoki et al.

2007). Curcumin-induced autophagy could be inhib-

ited by ROS scavenger N-acetylcystein in HCT116

cells, suggesting the involvement of ROS. However,

the ROS-dependent activation of ERK and p38 MAPK

is not involved (Lee et al. 2011). PD98059 (MEK1

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inhibitor) inhibits both curcumin-induced ERK path-

way and autophagy in SKN and SK-UT-1 cells (Liu

et al. 2013b), suggesting that ERK may also play a role

in this process.

Both autophagy and apoptosis are notably often

simultaneously observed after curcumin treatment

(Cheng et al. 2013; Jia et al. 2009; Kim et al. 2012a;

Qian et al. 2011), which suggests the existence of a

precisely controlled balance and a tight link between

them. Eukaryotic elongation factor-2 kinase (EEF2K)

is a critical controller of ER stress-induced autophagy

and apoptosis in cancer cells. The integrated regula-

tion of autophagy and apoptosis by EEF2K controls

cellular fate and modulates the efficacy of curcumin

and velcade (Cheng et al. 2013). Interestingly, curcu-

min-induced autophagy in glioma-initiating cells

promotes cell differentiation (Zhuang et al. 2012). A

functional link between senescence and autophagy in

curcumin-treated colon cells is also presented (Mos-

ieniak et al. 2012). Furthermore, curcumin induces

autophagy in human embryonic kidney cells (Ranjan

et al. 2014) and umbilical vein endothelial cells

(HUVECs) (Han et al. 2012). In addition, bis-dehy-

droxy-curcumin and tetrahydrocurcumin, the deriva-

tives and metabolites of curcumin, also induce

autophagy in human colon cancer cells and leukemia

HL-60 cells (Basile et al. 2013; Wu et al. 2011)

respectively.

Genistein

Genistein, the predominant isoflavone found in soy

products, has been shown to inhibit the carcinogenesis

in animal models. A growing body of evidence shows

that the inhibition of human cancer cell growth by

genistein is mediated via the modulation of genes that

are related to the control of cell cycle and apoptosis

(Banerjee et al. 2008). Genistein has been shown to

stimulate autophagy vacuolization (Singletary and

Milner 2008). In ovarian cancer cells, treatment with

genistein results in apoptosis and a caspase-indepen-

dent autophagic cell death (punctuate localization of

LC3) (Gossner et al. 2007). Co-treatment with I3C, a

compound derived from cruciferous vegetables, and

genistein, synergistically suppresses the viability of

human colon cancer HT-29 cells at concentrations at

which each agent alone is ineffective. The co-

treatment induces apoptosis through the simultaneous

inhibition of Akt activity and progression of the

autophagic process (Nakamura et al. 2009). Combi-

nation of LC3 shRNA plasmid transfection and

genistein treatment could inhibit autophagy and

increase apoptosis in human malignant neuroblastoma

both in cell culture and animal models (Mohan et al.

2013).

Kaempferol

Kaempferol, a dietary flavonoid rich in fruits and

vegetables, shows beneficial effects in reducing the

risk of chronic diseases, especially cancer (Chen and

Chen 2013). Kaempferol-induced autophagy is med-

iated by early activation of the AMPK/mTOR med-

iated pathway, which is an early and reversible process

occurring as survival mechanisms against apoptosis

mediated by mitochondrial pathway in HeLa cells.

Thus, autophagy is a survival response to kaempferol-

mediated energetic impairment (Filomeni et al. 2010).

While in human hepatic cancer SK-HEP-1 cells,

kaempferol causes autophagic cell death through

AMPK/Akt signaling pathway and induces G2/M

arrest via downregulation of CDK1/cyclin B (Huang

et al. 2013).

Oridonin

Oridonin, a diterpenoid isolated from Rabdosia rube-

scen (Hemsl.) Hara, presents potential anti-cancer

activities both in vitro and in vivo (Tan et al. 2011). It

arrests cancer cells at different phases due to the

various biological background and also triggers

apoptosis as well as autophagy (Li et al. 2011).

Oridonin induces autophagy in murine fibrosarcoma

L929 cells (Cheng et al. 2009), breast cancer MCF-7

cells (Cui et al. 2007a), epidermoid carcinoma A431

cells (Li et al. 2007a), cervical carcinoma HeLa cells

(Cui et al. 2007b), prostate cancer PC-3 cells and

LNCaP cells (Li et al. 2012; Ye et al. 2012),

fibrosarcoma HT-1080 cells (Zhang et al. 2009b),

histocytic lymphoma U937 cells (Zang et al. 2012),

and multiple myeloma RPMI8266 cells (Zeng et al.

2012).

Autophagic level is significantly up-regulated when

A431 and HeLa cells are pretreated with the Ras

specific inhibitor, manumycin A, compared with

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oridonin alone treatment, indicating Ras negatively

regulates autophagy in oridonin-treated cells (Cui

et al. 2007b; Li et al. 2007a). To be opposite, p38

MAPK and JNK inhibitors significantly decrease the

autophagy induced by oridonin in HeLa cells, indi-

cating the positive role of these MAPKs (Cui et al.

2007b). PKC enhances oridonin-induced autophagy

through regulating its downstream factors Raf-1 and

JNK in HeLa cells (Zhang et al. 2009a). Interestingly,

NF-jB promotes oridonin-induced apoptotic and

autophagic cell death through regulating P53 activa-

tion in HT1080 cells (Zhang et al. 2009b). Hydroxyl

radical may also play the pivotal role in oridonin-

induced autophagy in A431 cells (Yu et al. 2012).

In the condition of oridonin treatment, when

wortmannin (PI3K inhibitor) is applied, the autopha-

gic level is significantly decreased. While the apop-

totic level is increased indicating that PI3K is a key

regulator of both autophagy and apoptosis (Cui et al.

2006). It also indicates that inhibition of autophagy

contributes to the up-regulation of apoptosis in HeLa

cells (Cui et al. 2006). 3-MA pre-treatment increases

the apoptotic sensitivity of A431, L929, and PC-3 cells

to oridonin (Cheng et al. 2008; Li et al. 2007a, 2012).

The calcium-dependent cysteine protease, calpain,

promotes autophagy in oridonin-induced L929 cell

death and inhibition of autophagy contributes to up-

regulation of apoptosis (Cheng et al. 2008). However,

autophagy participates in up-regulation of apoptosis in

MCF-7 cells as 3-MA plus oridonin application down-

regulates DNA ladder and Bax expression compared

with oridonin alone (Cui et al. 2007a). Apoptosis and

autophagy are simultaneously induced by oridonin in

HT1080 cells and inhibition of autophagy decreases

oridonin-induced apoptosis, indicating that they act in

synergy to mediate cell death (Zhang et al. 2009b).

Paclitaxel

Paclitaxel, a mitotic inhibitor primarily targeting

microtubules, is a tetracyclic diterpenoid widely used

for the management of ovarian, breast, lung and head/

neck cancers. Paclitaxel treatment increases autopha-

gic activity in Saos-2 osteosarcoma cells and sup-

pressing autophagy by 3-MA enhances paclitaxel-

induced apoptosis. Therefore, autophagy observed

during paclitaxel-induced apoptosis represents the role

of cyto-protection in cellular homeostatic processes

(Kim et al. 2013). In A549 cells, paclitaxel treatment

induces autophagy and paclitaxel-mediated apoptotic

cell death is further potentiated by pretreatment with

3-MA or small interfering RNA against the autophagic

gene beclin1 (Liu et al. 2013a; Xi et al. 2011). ARHI, a

Ras-related imprinted gene that inhibits cancer cell

growth and motility, is essential for the induction of

autophagy in breast cancer cells. Paclitaxel alone does

not induce autophagy in breast cancer cells but

enhances ARHI-induced autophagy (Zou et al.

2011). Furthermore, it is suggested that paclitaxel

inhibits autophagy through two distinct mechanisms

dependent on the cell cycle stage: In mitotic cells, it

blocks the activation of class III PI3K and Vps34,

whereas in non-mitotic paclitaxel-treated cells, auto-

phagosomes are generated but their movement and

maturation is inhibited (Veldhoen et al. 2013).

Recent studies have revealed potential links

between autophagy modulation and paclitaxel resis-

tance. In MCF-7 cells, paclitaxel resistance is associ-

ated with profound changes in cell death response,

with the deletion of multiple apoptotic factors bal-

anced by the upregulation of the autophagic pathway.

Thus, switching from apoptotic to autophagic cell

death may be associated with paclitaxel resistance

(Ajabnoor et al. 2012). Furthermore, paclitaxel resis-

tance under hypoxia can be mediated by a more

effective autophagic flow activated through the classic

mTOR pathway and by a mechanism involving JNK,

which is dependent on Bcl-2 and Bcl-xL phosphory-

lation but independent of JNK-induced autophagy

activation (Notte et al. 2013).

Quercetin

Quercetin, another flavonoid similar to kaempferol in

structure, also presents anti-cancer activities in various

cancer cells by the oxidative, cell cycle-inhibitory, and

apoptosis-induction effects (Dajas 2012). A few

reports on quercetin-induced autophagic processes

are available. It induces autophagy in Ha-RAS-

transformed cells (Psahoulia et al. 2007) and human

gastric cancer AGS and MKN28 cells (Wang et al.

2011a). Exposure of gastric cancer cells to quercetin

results in appearance of autophagic vacuoles, forma-

tion of acidic vesicular organelles, conversion of LC3-

I to LC3-II, as well as activation of autophagy genes

(Wang et al. 2011a). Quercetin activates autophagy by

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modulation of Akt-mTOR and hypoxia-induced factor

1a signaling, which plays a protective role against it-

induced apoptosis in both AGS and MKN28 cells

(Wang et al. 2011a).

Resveratrol

Resveratrol is a natural phenol derived from a variety

of plants such as red grapes, blueberries, cranberries,

mulberries, lingonberries, peanuts, pistachios, pome-

granates, peanuts, cocoa and so on. Resveratrol, with

its anti-cancer, anti-inflammatory, neuro-protective,

and cardiovascular protective effects, has been con-

sidered a ‘‘famous star’’ natural product in the last

several decades. In terms of anti-cancer effect, resve-

ratrol is an inducer of multiple cell death pathways

including apoptosis, autophagy and mitotic catastro-

phe (Delmas et al. 2011). The regulation of autophagy

by resveratrol has been extensively investigated in

recent years, especially in cancer cells.

Opipari et al. (2004) firstly observed that resveratrol

treatment not only triggers the molecular features of

apoptosis but also induces autophagocytosis in human

ovarian carcinoma cell lines. This induction is due to

resveratrol’s inhibition of glucose metabolism medi-

ated by the down-regulation of phosphorylated Akt

and mTOR, two signals that increase glucose uptake

and the rate limiting steps in glycolysis (Kueck et al.

2007). Subsequent studies showed that resveratrol

regulates autophagy in human colorectal DLD1 cancer

cells (Trincheri et al. 2008), breast cancer cell lines

MCF-7, MDA-MB231 cells (Prabhu et al. 2013;

Scarlatti et al. 2008), cervical cancer cells (Garcia-

Zepeda et al. 2013; Hsu et al. 2009), gastric carcinoma

HGC-27 cells (Hsu et al. 2009), glioma cells (Filippi-

Chiela et al. 2011; Li et al. 2009; Lin et al. 2012;

Yamamoto et al. 2010), chronic myelogenous leuke-

mia cells (Puissant et al. 2010), hepatocellular carci-

noma Huh-7 cells (Liao et al. 2010), colon cancer HT-

29, COLO 201, HCT116 cells (Miki et al. 2012;

Prabhu et al. 2012), A431 SCC cells (Back et al. 2012),

prostate cancer C42B, PC3, and DU145 cells (Li et al.

2013), and esophageal squamous cell carcinoma

EC109 and EC9706 cells (Tang et al. 2013). Most of

the effect of resveratrol is autophagy promoting

whereas a few is autophagy inhibiting (Back et al.

2012; Lin et al. 2012) or inhibition of chemotherapy-

induced autophagy (Lin et al. 2012; Xu et al. 2012).

Resveratrol-induced autophagy may play dual roles:

Acting act as a pro-survival stress response at first and

switching to autophagic apoptosis pathway at a later

time (Trincheri et al. 2008). The diverse signaling

pathways involved in resveratrol-induced autophagy

have been identified by increasing cytosolic expres-

sion and activity of lysosomal enzyme cathepsin L

(Hsu et al. 2009); by the accumulation of intracellular

dihydroceramide levels through the inhibition of

dihydroceramide desaturases activity (Signorelli

et al. 2009); by activating JNK-mediated p62/

SQSTM1 expression and AMPK activation (Puissant

et al. 2010); by regulating p38 MAPKand the ERK

pathway (Yamamoto et al. 2010); by inhibiting both

mTOR and p70S6K and to activate AMPK (Puissant

and Auberger 2010); by the increased expression of

autophagy-related Atg5, Atg7, Atg9, and Atg12 pro-

teins (Liao et al. 2010); by inducing the intracellular

ROS formation (Miki et al. 2012). Mutation in p53 and

human papillomavirus (HPV) infection may also be

potential effectors (Garcia-Zepeda et al. 2013). As

mentioned above, mTOR and Beclin 1 play key roles

in classic autophagy pathways, whereas evidence

suggests that resveratrol-induced autophagy in some

cancer cells is independent of AMPK/mTOR or Akt/

mTOR pathways (Tang et al. 2013; Yamamoto et al.

2010) and may occur in a non-canonical Beclin

1-independent manner (Scarlatti et al. 2008). Further-

more, the involvement of SIRT1, a potential molecular

target for resveratrol, remains controversial (Armour

et al. 2009; Bjorklund et al. 2011; Li et al. 2013).

In terms of autophagy inhibitory effect, the resve-

ratrol-induced premature senescence of human A431

SCC cells is associated with a blockade of autolyso-

some formation, which is mediated by the down-

regulation of the level of Rictor, a component of

mTORC2 (Back et al. 2012). Resveratrol inhibits

doxorubicin-induced cardiomyocyte death by the

inhibition of p70S6K1-mediated autophagy (Xu

et al. 2012). More importantly, resveratrol demon-

strates a synergistic effect with temozolomide (TMZ)

by enhancing TMZ-induced apoptosis through the

suppression of cytoprotective autophagy as mediated

by a ROS burst and ERK activation both in vitro and

in vivo (Lin et al. 2012).

The interplay of autophagy with apoptosis is

commonly evidenced by the fact that resveratrol-

induced apoptosis is enhanced by the inhibition of

autophagy (Prabhu et al. 2012; Tang et al. 2013), the

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autophagic apoptosis (Miki et al. 2012). Moreover,

resveratrol-induced apoptosis is dependent on the lipid

kinase activity of Vps34 and on the formation of

autophagolysosomes in human colorectal cancer

DLD1 cells (Trincheri et al. 2008).

Silybin

Silybin or silibinin, a flavonolignan isolated from milk

thistle (Silybum marianum) seeds, is a mixture of two

diastereomers, silybin A and silybin B, in approximate

equimolar ratio (Agarwal et al. 2013). Besides the

well-documented hepatoprotective properties (Logu-

ercio and Festi 2011), the therapeutic potential of

silybin against cancer is also accumulated in recent

years and is of interest among many researchers

(Cheung et al. 2010; Deep and Agarwal 2010).

Silibinin shows significant inhibitory effect on cancer

cell proliferation by induction of both autophagic and

apoptotic cell death, which is dependent on ROS in

fibrosarcoma HT1080 cells (Duan et al. 2010). The

autophagic cell death is mediated by P53 through

activating ROS-p38 MAPK and JNK pathways, as

well as inhibiting MEK/ERK and PI3K/Akt pathways

in HT1080 cells (Duan et al. 2011a, b). Similarly, the

inhibitory effects of silibinin on HeLa cells growth

caused by autophagy and apoptosis is mediated by

ROS and reactive nitrogen species (RNS) generation

(Fan et al. 2011). The ROS generation induced by

silibinin is mediated by P53 activation in epidermoid

carcinoma A431 cells (Fan et al. 2012). In colorectal

cancer SW480 cells, silibinin rapidly induces ROS

generation, dissipation of mitchondrial potential

(DWm) and cytochrome c release leading to mild

apoptosis. However, increased exposure to silibinin

partly reversed the apoptotic response and increased

autophagic events by inhibiting PIK3CA-Akt-mTOR

but activating MAP2K1/2-MAPK1/3 pathways (Raina

et al. 2013).

Triptolide

Triptolide, a diterpene triepoxide extracted from the

Chinese herb Tripterygium wilfordii Hook. F., is a

toxic compound with potent anti-inflammatory,

immune modulation, and anti-cancer effect (Liu

2011; Wong et al. 2012). Triptolide-induced

autophagy is observed in pancreatic cancer cells

(Mujumdar et al. 2010), lung cancer A549 cells

(Zhang et al. 2012a), neuroblastoma SH-SY5Y and

IMR-32 cells (Krosch et al. 2013). Triptolide-induced

pancreatic cancer cells autophagy is a pro-death effect,

required autophagy-specific genes, Atg5 or Beclin1,

and is associated with the inactivation of the Akt/

mTOR/p70S6K1 pathway and the up-regulation of the

ERK pathway (Mujumdar et al. 2010). While in A549

cells, triptolide induces cell death predominantly

through activation of autophagy instead of apoptosis

due to the suppressive effect of 3-MA, significant

increase of LC3-II protein expression and the failure

of visible sign of apoptosis (Zhang et al. 2012a). In

SH-SY5Y and IMR-32 cells, triptolide induces both

apoptotic and autophagic pathways and results in

inhibition of NF-jB activity (Krosch et al. 2013). In

addition, severe heat causes cell damage, apoptosis

and autophagy in H9c2 cardiomyocytes. Triptolide

pretreatment significantly attenuates mild heat pre-

conditioning induced beneficial effects of preventing

heat-induced cell damage, apoptosis and autophagy by

inhibiting HSP70 overexpression (Hsu et al. 2013).

Ursolic acid

Ursolic acid, a natural pentacyclic triterpenoid, shows

potent cytotoxic, anti-cancer, antioxidant, anti-inflam-

matory, anti-microbial, and hepatoprotective activi-

ties. Furthermore, human clinical trials of ursolic acid

for treating cancer and skin wrinkles are in progress

(Sultana 2011). Effect of ursolic acid on autophagy has

been documented. In PC3 prostate cancer cells, ursolic

acid-induced autophagy is mediated through the

Beclin-1 and Akt/mTOR pathways and functioned as

a survival mechanism against it-induced apoptosis

(Shin et al. 2012). Autophagy is found to be the major

mechanism of ursolic acid-induced TC-1 cervical

cancer cells death since no apoptosis is detected after it

treatment. Atg5, rather than Beclin-1, is confirmed to

play a crucial role in this process (Leng et al. 2013). In

HCT15 p53 mutant apoptosis-resistant colorectal

cancer cells, ursolic acid-induced caspases-indepen-

dent apoptosis accounts for a small percentage of total

cell death. The modulation of autophagy by ursolic

acid through induction of LC3 accumulation and p62

levels with involvement of JNK pathway is the major

cause of cell death (Xavier et al. 2013). Ursolic acid

Phytochem Rev

123

induces ER stress, autophagy, and apoptosis in MCF-7

breast cancer cells. Interestingly, ER stress is found to

be the consequence rather than the cause of autophagy.

Furthermore, this autophagy-dependent ER stress

protects the cells from ursolic acid-induced apoptosis

through EIF2AK3-mediated upregulation of MCL1.

In addition, the cyto-protective autophagy was med-

iated by activation of MAPK1/3 but not inhibition of

mTOR pathway (Zhao et al. 2013).

The potential actions and mechanisms of the natural

autophagy regulators discussed above are briefly

summarized as Fig. 2. The exploration of natural

products-induced autophagy in depth has been ongo-

ing only in recent few years; thus, limited data is

available at present. However, this area progresses

very quickly and aside from the autophagy regulators

mentioned above, more and more natural autophagic

regulators have been identified. Their chemical struc-

tures and underlying mechanisms are briefly summa-

rized in Fig. 3 and Table 1.

Conclusion and perspective

Autophagy is the most interesting research topic in the

biological and pharmacological areas in recent years.

Compared with our exhaustive understanding of

apoptosis, autophagy is still in its infancy and

sustained efforts are urgently needed to uncover the

detailed signaling pathways, physiological, and path-

ological significance of autophagy. This essential,

conserved, and complicated homeostatic cellular

recycling mechanism/pathway will provide potential

therapeutic targets for diverse diseases, especially for

Fig. 2 The molecular mechanisms of representative natural

products on autophagy. AKT protein kinase B; AMPK adenosine

50-monophosphate (AMP)-activated protein kinase; Atg autoph-

agy-related gene; ERK extracellular signal-regulated kinases;

mTOR mammalian target of rapamycin; JNK c-Jun NH2-

terminal kinases; MAPK mitogen-activated protein kinases;

PI3K phosphoinositide 3-kinase; PKC protein kinase C; p70s6k

ribosomal protein S6 kinase, 70 kDa; ROS reactive oxygen

species; Ras ras protein; Sirt1 sirtuin type 1; VPS34 vacuolar

protein sorting 34

Phytochem Rev

123

Fig. 3 Chemical structures of natural plant derived autophagy-regulators

Phytochem Rev

123

anti-cancer therapy, similar to apoptosis (Janku et al.

2011). Although the precise roles of autophagy in

cancer are still controversial due to its paradoxical

roles in cell survival and death (Dziedzic and Caplan

2012; Moreau et al. 2010; Shen and Codogno 2011),

promising attempts at anti-cancer treatment through

Fig. 3 continued

Phytochem Rev

123

Table 1 Autophagy regulators from natural products and their actions and underlying mechanism (Those discussed in detail in the

main text are not included)

Compound Cancer cell line Action and mechanism References

Allicin Hep G2 ; cytoplasmic p53, PI3K/mTOR, Bcl-2; : AMPK/TSC2

and Beclin-1

Chu et al. (2012)

a-Mangostin Her/CT26, CML Reduced ER stress; autophagy inhibition augments the

anti-cancer activity

Chen et al. (2014); Kim

et al. (2012b)

Anthocyanin PLC/PRF/5, HepG2 Autophagy inhibition enhances apoptosis Longo et al. (2008)

Baicalin SMMC-7721, T24 Downregulation of CD147 and the Akt signaling

pathway

Lin et al. (2013); Zhang

et al. (2012c)

Celastrol HeLa, A549, PC-3 Induction of paraptosis, autophagy and apoptosis Wang et al. (2012)

Camptothecin MCF-7 Induction of autophagy and apoptosis by regulation of

BID

Lamparska-Przybysz et al.

(2005)

Cucurbitacin B HeLa Induction of mitochondrial ROS production Zhang et al. (2012b)

Jurkat G-actin reduction and cofilin activation Zhu et al. (2012)

Dihydrocapsaicin H1299, H460, A549,

CT116, MCF-7

Induction of catalase-mediated autophagy Choi et al. (2010b); Oh

et al. (2008)

Dioscin Huh7 Induction of pro-survival autophagy Hsieh et al. (2012)

Evodiamine SGC-7901, HeLa Induction of ROS and NO generations Rasul et al. (2012); Yang

et al. (2008)

Fisetin MCF-7 Inhibition of autophagy in caspase-3-deficient cancer

cells

Yang et al. (2012)

Flavokawain B HCT116 ROS generation and GADD153 up-regulation Kuo et al. (2010)

[6]-Gingerol HeLa Induces autophagy and caspase 3 mediated apoptosis Chakraborty et al. (2012)

Ginsenoside F2 Breast cancer stem cells Induction of apoptosis and autophagy Mai et al. (2012)

Ginsenoside Rk1 HepG2 Induction of pro-survival autophagy Ko et al. (2009)

Helenalin A2780, RKO, MCF-7 Induction of autophagy by inhibition of NF-jB p65 Lim et al. (2012)

Honokiol DBTRG-05MG Induction of apoptosis and autophagy Chang et al. (2013)

Isobavachalcone H929 Autophagy inhibition enhances cell death Zhao et al. (2012)

Licorice

licochalcone-A

LNCaP Suppression of Bcl-2 expression and the mTOR

pathway

Yo et al. (2009)

Luteolin H460 Triggers ER stress-related apoptosis and autophagy Park et al. (2013)

Magnolol H460 Induces autophagy without apoptosis by blockade of

PI3K/PTEN/Akt

Li et al. (2007b)

Matrine SGC7901 An autophagy inhibitor modulates the maturation

process of lysosomal proteases

Wang et al. (2013)

Neferine A549 Induces autophagy through ROS and inhibition of

PI3K/Akt/mTOR

Poornima et al. (2013)

Ophiopogonin B H157, H460 Induction of autophagy without apoptosis by inhibition

of PI3K/Akt

Chen et al. (2013)

Pheophorbide-a MDA-MB-231 Enhance apoptosis by suppression of ERK-mediated

autophagy

Bui-Xuan et al. (2010)

Piperine DU145, PC-3, LNCaP Induces cell cycle arrest and autophagy Ouyang et al. (2013)

Salidroside UMUC3 Inhibition of the mTOR pathway and induction of

autophagy

Liu et al. (2012b)

Triterpenes HT-29 Induces autophagy through inhibition of p38 MAPK Thyagarajan et al. (2010)

Wogonin NPC Induces autophagy and apoptosis through Akt pathways Chow et al. (2012)

Wogonoside MDA-MB-231 Induces autophagy by inhibiting mTOR through MAPK Sun et al. (2013)

Phytochem Rev

123

autophagy modulation are already in progress. How-

ever, the inconsistent fact that numerous anti-cancer

compounds could affect the autophagy process either

by promotion or inhibition may complicate the

philosophy of this issue. From drug discovery point

of view, autophagy induction may be a feasible

direction. As most of these actions are cyto-protective

or apoptosis-stimulative, two possible strategies may

be applied during drug design and screening: the

inhibition of protective autophagy and the enhance-

ment of stimulative autophagy. Although many of the

natural products have shown anti-cancer effects both

in vitro and in vivo, their mechanisms of action remain

unclear and their efficacy is relatively low in general.

The role of natural products in apoptosis has been well

established whereas their effect on autophagy has just

been recognized in recent years. There is sufficient

reason to believe that autophagy plays a role in natural

products’ anti-cancer effect. Furthermore, compounds

targeted autophagy may represent a novel class of anti-

cancer agents in the future.

Acknowledgments The present study was supported by the

grant from the Science and Technology Development Fund of

the Macau Special Administrative Region (No. 021/2012/A1,

070/2013/A) and the Research Fund of the University of Macau

(No. MRG007/CXP/2013/ICMS, MYRG118(Y1-L4)-ICMS13-

CXP).

Conflict of interest We declare that none of the authors have

any kind of conflict of interest related to the present work.

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