Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies
Abstract
:1. Introduction
2. Polyphenols
3. In Vitro- and In Vivo-Mediated Autophagy by Polyphenols
3.1. Flavonoids
3.1.1. Flavonols
3.1.2. Flavan-3-ols
3.1.3. Flavones
3.1.4. Anthocyanins
3.1.5. Flavanones
3.1.6. Isoflavones
3.2. Non-Flavonoids
3.2.1. Coumarins
3.2.2. Curcuminoids
3.2.3. Phenolic Acids
3.2.4. Lignans
3.2.5. Stilbenes
3.2.6. Xanthones
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Polyphenol | In Vitro Model | In Vivo Model | Effects on Autophagy | Reference |
---|---|---|---|---|
Flavonoids | ||||
Flavonols | ||||
Quercetin | MCF-7 breast cancer cells and HeLa cervical cancer cells (90 µM) | Induction of autophagy ↑ Autophagosomes and autolysosomes ↓ mTOR pathway | [58] | |
Burkitt lymphoma cells (100 µM) | Induction of autophagy ↑ LC3 II expression ↓ PI3K/Akt/mTOR pathway | [59] | ||
MCF-7 and MDA-MB-231 breast cancer cells (30 µM) | BALB/c nude mice s.c. injected with MCF-7 cells (50 mg/kg, i.p., twice daily) | Induction of autophagy ↑ LC3 II/I ratio ↑ LC3-puncta structures ↓ Akt/mTOR pathway | [60] | |
A549 NSCLC cells (20–80 µM + TRAIL) | Induction of autophagy ↑ LC3 II expression ↑ Autophagosomes ↓ Akt/mTOR pathway ↑ TRAIL-induced cell death | [61] | ||
NOD/SCID mice s.c. injected with HL-60 AML cells (Quercetin 120 mg/kg, i.p., every 4 days; green tea: 100 mg/kg, p.o., daily) | Induction of autophagy ↑ Beclin 1, ATG7, ATG5-ATG12 expression ↑ LC3 II positive cells | [62] | ||
MOGGCCM anaplastic astrocytoma and T98G glioblastoma multiforme (30–50 µM + Sorafenib) | Induction of autophagy ↑ AVOs ↑ Beclin 1 and LC3 II expression | [63] | ||
U373MG malignant glioma cells (25–100 µM) | Induction of cytoprotective autophagy ↑ AVOs ↑ LC3 I to LC3 II conversion | [64] | ||
U87 and U251 glioma cells (25–100 µM) | Sprague Dawley rats intracranially injected with rat glioma C6 cells (100 mg/kg, i.v., daily) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ LC3 II expression | [65] | |
AGS and MKN28 gastric cancer cells (AGS: 10–40 µM; MKN28: 40–160 µM) | BALB/c mice s.c. injected with MKN28 cells (50 mg/kg, i.p., daily) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ AVOs ↑ LC3 I to LC3 II conversion ↑ Beclin 1, ATG7, ATG5-ATG12 expression ↓ Akt/mTOR pathway | [66] | |
BC3 and BCBL1 primary effusion lymphoma cells (50 µM) | Induction of cytoprotective autophagy ↑ LC3-puncta structures ↑ LC3 II expression ↓ PI3K/Akt/mTOR pathway | [67] | ||
CAOV-3 and primary P#1 ovarian cancer cells (40–80 µM) | NOD/SCID mice i.p. injected with CAOV-3 cells (80 mg/kg, i.p., twice a week) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion ↑ Beclin 1 and ATG5 expression | [68] | |
P39 leukemia cells (50 µM) | Induction of cytoprotective autophagy | [69] | ||
HL-60 AML cells (100 µM) | Induction of cytoprotective autophagy | [70] | ||
HeLa cervical cancer cells (50 µM) | Induction of cytoprotective autophagy | [71] | ||
CHNQ | HCT-116 and HT-29 colon cancer cells (HCT-116: 25 µM) (HT-29: 40 µM) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3-puncta structures ↑ AVOs ↓ Akt phosphorylation | [72] | |
8-CEPQ | SW620 and HCT-116 colon cancer cells (15 µM) | Induction of autophagy ↑ AVOs ↑ LC3-puncta structures ↑ LC3 II, Beclin 1 and ATG7 expression ↓ p62 expression ↑ ERK pathway | [73] | |
GQ | A549 and NCI-H1975 NSCLC cells (25–35 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II and Beclin 1 expression ↓ p62 expression | [74] | |
Hyperoside | A549 NSCLC cells (0.5–2 mM) | Induction of autophagy ↑ LC3 II expression ↑ Autophagosomes ↓ p62 expression ↓ Akt/mTOR/p70S6K pathway ↑ ERK pathway | [75] | |
SKOV-3 and HO-8910 ovarian cancer cells (50–100 µM) | Induction of autophagy ↑ MDC-labelled vacuoles ↑ LC3 II expression | [76] | ||
Isorhamnetin | A549 NSCLC cells (2–8 µM) | BALB/c nu/nu mice s.c. injected with A549 cells (0.5 mg/kg, i.p., daily) | Induction of cytoprotective autophagy ↑ LC3 II and Beclin 1 expression ↑ LC3-puncta structures ↑ MDC-labelled vacuoles | [77] |
Rutin | D54MG glioblastoma multiforme cells (50–200 µM + TMZ) | BALB/c athymic mice s.c. injected with U87 glioma cells or intracranially injected with U87 cells (20 mg/kg, i.p., daily) | Inhibition TMZ-induced autophagy ↓ LC3 II expression ↓ JNK activity ↑ Drug-induced cytotoxicity | [78] |
Taxifolin | HeLa cervical cancer cells (100 µM + Andrographolide) | Inhibition andrographolide-induced autophagy ↓ LC3-puncta structures ↓ AVOs ↑ Drug-induced cytotoxicity | [79] | |
Quercetin nanoparticles (NPs) | U87 glioma cells (30–40 µg/mL) | BALB/c nu/nu nude mice s.c. injected with U87 cells (40 and 80 mg/kg, i.p., daily) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ Beclin 1 expression ↓ p62 expression ↓ Akt/mTOR pathway | [80] |
Caski cervical cancer cells (10–20 µg/mL) | BALB/c nu/nu nude mice s.c. injected with Caski cells treated with NPs | Induction of autophagy ↑ Autophagosomes ↓ Akt/mTOR pathway | [81] | |
Kaempferol | SK-Hep-1 HCC cells (50–100 µM) | Induction of autophagy ↑ Autophagosomes ↑ AVOs ↑ LC3-puncta structures ↑ LC3 II, ATG5, ATG7, ATG12 and Beclin 1 expression ↓ Akt/mTOR pathway | [82] | |
A549 NSCLC cells (20–50 µM) | Induction of autophagy ↑ LC3 II/I ratio ↑ ATG7 and Beclin 1 expression ↓ p62 expression ↑ LC3-puncta structures ↓ PI3K/Akt pathway | [83] | ||
SNU-216 gastric cancer cells (50 µM) | Induction of autophagy ↑ LC3 II/I ratio ↑ ATG7 and Beclin 1 expression ↓ p62 expression | [84] | ||
AGS and SNU-638 gastric cancer cells (50 µM) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3 II, Beclin 1 and ATG5 expression ↓ p62 expression ↑ LC3-puncta structures | [85] | ||
Kaempferol or CAPE | RKO and HCT-116 colon cancer cells (RKO: CAPE 36.87 µM, kaempferol 17.42 µM) (HCT-116: CAPE 3.326 µM, kaempferol 9.427 µM) | Induction of autophagy ↑ MDC-labelled vacuoles | [86] | |
Juglanin | MCF-7 and SK-BR-3 breast cancer cells (2.5–10 µM) | BALB/c-nude mice s.c. injected with MCF-7 cells (5 and 10 mg/kg, i.p., daily) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression | [87] |
Kazinol A | T24 and cisplatin-resistant T24R2 bladder cancer cells (20 µM) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion ↓ mTOR phosphorylation | [88] | |
Dihydromyricetin | A431 epidermoid carcinoma cells (25–100 µM) | Induction of autophagy ↑ Beclin 1 and LC3 II expression | [89] | |
HepG2 HCC cells (10–50 µM) | Induction of autophagy ↑ Beclin 1 and LC3 II expression | [90] | ||
SK-MEL-28 human melanoma cells (100 μM) | Induction of cytoprotective autophagy ↑ Beclin 1 and LC3 II expression ↓ p62 expression Activation NF-κB pathway | [91] | ||
CAL-27 OSCC cells (50 μM) | Induction of cytoprotective autophagy ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [92] | ||
Flavan-3-ols | ||||
HLP extract and ECG | A375 melanoma cells (HLP: 100–250 μg/mL; ECG: 100 µM) | Induction of autophagy ↑ AVOs ↑ LC3 II, Beclin 1, ATG9, ATG16, ATG5-ATG12 expression ↓ Akt/mTOR pathway | [93] | |
EGCG | SSC-4 OSCC cells (20 µM) | Induction of autophagy ↑ MDC-labelled vacuoles | [94] | |
4T1 breast cancer cells (10, 20, 40 µM) | BALB/c mice s.c. injected with 4T1 cells (5, 10, 20 mg/kg, i.p., daily) | Induction of autophagy ↑ LC3 II/I ratio, Beclin 1, ATG5 expression ↑ LC3-puncta structures ↑ Autophagosomes | [95] | |
HepG2 HCC cells (25–50 µM) | Induction of autophagy ↑ MDC-labelled vacuoles ↑ LC3-puncta structures ↑ LC3 II expression Degradation of AFP aggregates | [96] | ||
HCT-116 colorectal cancer cells (12.5 µM + 2 Gy radiation) | Induction of autophagy ↑ LC3 II mRNA expression ↑ Sensitivity to radiation | [97] | ||
HepG2 HCC cells PANC-1 pancreatic cancer cells (20 µM + PEF + US) | Induction of autophagy ↑ MDC-labelled vacuoles ↑ LC3 II expression ↓ Akt phosphorylation | [98] | ||
GBM15, GBM16 primary glioblastoma cells (500 µM) | Induction of autophagy ↑ MDC-labelled vacuoles ↑ LC3 II expression | [99] | ||
EHMES-10, ACC-meso and Y-meso malignant mesothelioma cells (50–250 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression | [100] | ||
JP8 | B16-F10 melanoma cells (20 µM) | C57BL/6 mice s.c. injected with B16-F10 cells (25 and 50 mg/kg, i.p., daily) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3-puncta structures ↓ p62 expression | [101] |
Green tea extract | A549 NSCLC cells (25, 50, 150 µM) | Induction of cytoprotective autophagy ↑ Autophagosomes and autolysosomes ↑ AVOs ↑ LC3-puncta structures | [102] | |
Polyphenon E® | PNT1a prostate cancer cells (35 µg/mL) | Induction of cytoprotective autophagy ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion | [103] | |
Tea polyphenols + anticancer drugs | T24 cells and BIU87 bladder cancer cells (100 µM + Epirubicin) | Inhibition epirubicin-induced autophagy ↓ LC3 II induction ↓ Autophagosomes and autolysosomes ↑ Sensitivity to epirubicin | [104] | |
PC-3 and DU145 castration-resistant prostate cancer cells (20 µM + Docetaxel) | Inhibition docetaxel-induced autophagy ↓ LC3 II expression ↑ mTOR activation ↑ Sensitivity to docetaxel | [105] | ||
EGCG + anticancer drugs | Hep3B hepatoma cells (10–40 µg/mL + DOX) | Nude mice s.c. injected with Hep3B cells (50 mg/kg, intragastric, daily + DOX) | Inhibition DOX-induced autophagy ↓ Autophagosomes ↓ ATG5, Beclin 1 mRNA and protein ↑ Sensitivity to DOX | [106] |
SaoS2 and U2OS cells osteosarcoma cells (20 µg/mL + DOX) | Inhibition DOX-induced autophagy ↓ LC3-puncta structures ↓ ATG5, Beclin 1 mRNA ↓ LC3 II/I ratio ↑ p62 expression ↑ Sensitivity to DOX | [107] | ||
A549 NSCLC cells (34 µM + Gefitinib) | Inhibition gefitinib-induced autophagy ↓ LC3-puncta structures ↓ LC3 II/I ratio, ATG5 expression ↑ p62 expression ↑ Sensitivity to gefitinib | [108] | ||
DLD-1 and HT-29 colon cancer cells (100 µM + Cisplatin/Oxaliplatin) | ↑ Drugs-induced autophagy ↑ LC3 I to LC3 II conversion ↑ LC3 II expression ↑ Autophagosomes ↑ AVOs | [109] | ||
Cisplatin-resistant CAR oral cancer cells (50 µM) | Induction of autophagy ↑ AVOs ↑ Autophagosomes ↑ LC3-puncta structures ↑ ATG5, ATG7, ATG12, Beclin 1 and LC3 II expression ↓ Akt/STAT3 pathway | [110] | ||
PC-3 prostate cancer cells (5, 50 µM + Bortezomib) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion Antagonized drug-induced cytotoxic effect | [111] | ||
HCT-116 colorectal cancer cells (5–20 µM + TRAIL) | Induction of autophagy ↓ p62 expression and accumulation Antagonized drug-induced cytotoxic effect | [112] | ||
Flavones | ||||
Isocannflavin B | Estrogens sensitive ER+ T47-D and insensitive ER− MDA-MB-231 cells (25 µM) | Induction of autophagy in ER+ cells | [113] | |
Apigenin | Primary epidermal keratinocytes and COLO16 cutaneous squamous cell carcinoma cells (20–80 µM + UVB) | Restoring of autophagy ↑ LC3 II | [114] | |
TF1 erythroid subtype leukemia cells (100 µM) | Induction of autophagy ↑ ATG5, ATG12 expression | [115] | ||
MM-F1, MM-B1 and H-Meso-1 malignant mesothelioma cells (50 μM) | No effects on autophagy | [116] | ||
HT-29 colon cancer cells (15–60 µM) | Induction of autophagy ↑ Autophagosomes ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [117] | ||
BCPAP papillary thyroid carcinoma cells (12.5–50 µM) | Induction of autophagy ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [118] | ||
HepG2 HCC cells (10–40 µM) | Induction of cytoprotective autophagy ↑ LC3 II, ATG5 and Beclin 1 expression ↓ PI3K/Akt/mTOR pathway | [119] | ||
HCT-116 colon cancer cells (6.25–50 µM) | Induction of cytoprotective autophagy ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [120] | ||
Wogonin | NPC-TW076 and NPC-TW039 nasopharyngeal carcinoma cells (50 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression ↑ Autophagosomes and autolysosomes ↓ Akt/cRaf/ERK pathway | [121] | |
SW48 colorectal cancer cells (4–16 µM) | Induction of autophagy ↑ Beclin 1 and LC3 II | [122] | ||
BGC-823 gastric cancer cells (10, 50 and 200 µM + Oxaliplatin) | Induction of autophagy ↑ LC3 II | [123] | ||
Baicalein | SMMC-7721 and Bel-7402 HCC cells (100 and 200 µM) | Induction of cytoprotective autophagy ↑ LC3 II | [124] | |
HepG2 HCC cells (12.5–50 µM) | Induction of cytoprotective autophagy ↓ Akt/mTOR pathway | [125] | ||
HEY and A2780 ovarian cancer cells (12.5–50 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression and AVOs | [126] | ||
CAL-27 OSCC cells (25–100 µM) | Induction of cytoprotective autophagy ↑ LC3 II, Beclin 1 and p62 | [127] | ||
U251MG glioma cells (10–80 µM) | Induction of autophagy ↑ LC3 II expression ↑ AMPK pathway | [128] | ||
Follicular undifferentiated thyroid cancer cells (10–80 µM) | Induction of autophagy ↑ p62, Beclin 1, ATG5, ATG12 expression | [129] | ||
PC-3, MDA-MB-231 and DU145 cancer cells (5 µg/mL) | Induction of autophagy ↑ Autophagosomes ↑ AMPKα and ULK1 ↓ mTOR and Raptor | [130] | ||
MCF-7 and MDA-MB-231 breast cancer cells (10, 20, 40 µM) | BALB/c-nude mice s.c. injected with MCF-7 or MDA-MB-231 cells (100 mg/kg, p.o., daily) | Induction of autophagy ↑ LC3 II and Beclin 1 expression ↓ PI3K/Akt pathway | [131] | |
Stem cell-like cells (TICs) isolated from mouse and human liver tumors (30 µM) | Inhibition of autophagy ↓ Autophagosomes formation ↓ GTP binding of SAR1B GTPase | [132] | ||
Polymethoxyflavone 5-demethylnobiletin (5-DMN) | CL1-5 and A549 NSCLC cells (12.5 μM) | Induction of cytoprotective autophagy ↑ Beclin 1 expression | [133] | |
Luteolin | MET4 cells derived from a primary cutaneous invasive squamous cell carcinoma (50 µM) | Induction of cytoprotective autophagy ↑ Autophagosomes ↓ p62 expression | [134] | |
NCI-H460 NSCLC cells (200 µM) | Induction of autophagy ↑ LC3B II expression | [135] | ||
Huh7 HCC cells (20 µM) | Induction of autophagy ↑ LC3 II expression ↓ p62 expression | [136] | ||
SMMC-7721 HCC cells (25–100 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3B II and Beclin 1 expression | [137] | ||
Luteolin and Silibinin | U87MG and T98G glioma cells (Luteolin: 20 µM; Silibinin: 50 µM) | Inhibition of autophagy ↓ Beclin 1, LC3B I and II expression | [138] | |
Salvigenin | SH-SY5Y neuroblastoma cells (25–50 µM) | Induction of cytoprotective autophagy ↑ LC3 II/I ratio ↑ ATG7 and ATG12 expression | [139] | |
Baicalin | SMMC-7721 HCC cells (40–160 µM) | Induction of autophagy ↑ Beclin 1 expression | [140] | |
Human bladder cancer T24 cells (100–200 µM) | Induction of autophagy ↓ p-Akt (Ser473) protein level and Akt kinase activity ↑ ATG complex, LC-3 and Beclin 1 expression | [141] | ||
Diosmin | MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cells (5–20 μM) | Induction of cytostatic and cytotoxic autophagy ↑ Oxidative stress and DNA damage | [142] | |
Seed extract from Euterpe oleracea Mart. | MCF-7 breast cancer cells (10, 20 and 40 μg/mL) | Induction of autophagy ↑ LC3B II expression | [143] | |
Delicaflavone | A549 and PC-9 NSCLC cells (40 μg/mL) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II/I ratio ↓ p-Akt, p-mTOR and p-p70S6K | [144] | |
Luteoloside | A549 and H292 NSCLC cells (60 µM) | Induction of autophagy ↓ Akt/mTOR/p70S6K signaling pathway ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [145] | |
Glychionide-A | PANC-1 pancreatic cancer cells (7–28 µM) | Induction of autophagy ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [146] | |
Isoorientin | HepG2 HCC cells (20–80 μM) | Induction of autophagy ↑ Beclin 1 and LC3 II expression | [147] | |
Isovitexin | HepG2 and SK-Hep-1 HCC cells (12.5–50 μg/mL) | Induction of autophagy ↑ Beclin 1, LC3B II, ATG3 and ATG5 expression | [148] | |
Wogonoside | U251MG and U87MG glioma cells (250–300 µM) | Induction of autophagy ↑ AVOs ↑ LC3 II expression ↓ p62 expression ↑ p38 MAPK ↓ PI3K/Akt/mTOR/p70S6K pathways | [149] | |
Nobiletin | CAOV-3 and ES-2 ovarian cancer cells (40 μM) | Induction of autophagy ↑ p62 expression | [150] | |
SNU-16 gastric cancer cells (12.5–50 μM) | Induction of autophagy ↑ LC3 II/I ratio ↓ p62 expression | [151] | ||
Zapotin | HeLaPKCeA/E cancer cells with overexpressed constitutively active protein kinase C epsilon (30 μM) | Inhibition of autophagy ↓ Autophagosomes formation ↓ LC3 expression | [152] | |
Vitexin | SK-Hep-1 and Hepa1-6 HCC cells (100 µM) | Inhibition of cytoprotective autophagy ↓ LC3 II expression | [153] | |
Anthocyanins | ||||
Delphinidin | MDA-MB-453 and BT474 HER-2+ breast cancer cells (MDA-MB-453: 80 µM) (BT474: 140 µM) | Induction of autophagy ↑ Autophagic vacuoles ↑ LC3 II expression ↑ ATG5-ATG12 expression ↓ p-Akt, p-mTOR, p70S6K, eIF4E ↑ LKB1, AMPK, ULK1, FOXO3a | [154] | |
SMMC7721, HCCLM3 and MHCC97L HCC cells (80–150 µM) | Induction of autophagy ↑ Autophagic vacuoles ↑ LC3 II expression | [155] | ||
U2OS osteosarcoma cells (10–200 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression ↓ p62 expression | [156] | ||
HeLa cervical cancer cells (100 µM) | ATG5-deficient mouse embryonic fibroblasts (100 µM) | Induction of autophagy ↑ Autophagosomes and autolysosomes ↑ Colocalization LC3 II/LAMP-1
↓ Autophagy | [157] | |
Pelargonidin | U2OS osteosarcoma cells (15–30 µM) | Induction of autophagy ↑ Beclin 1 and LC3 II expression ↓ LC3 I expression ↓ p-PI3K, p-Akt ↑ ROS | [158] | |
Cyanidin | 786-O and ACHN RCC (25–100 µM) | ↓ ATG4, p62 expression ↓ LC3 II expression ↑ EGR1, SEPW1 expression | [159] | |
C3G | INS-1 rat pancreatic β cells under oxidative stress condition (H2O2 treatment) (0.5–1 µM) | Reduction in H2O2-induced autophagy ↓ LC3 II expression ↓ Autophagic vacuoles ↓ MDC-labelled vacuoles ↑ HO-1, Nrf2 | [160] | |
Polyphenols from Mulberry water extract (MPE) | p53+ HepG2 and p53− Hep3B HCC cells (0.25–1 mg/mL) | DEN-induced liver cancer in Wistar rat fed with normal diet + 1–2% MPE | ↑ Apoptosis of p53+ HepG2 ↑ Autophagy of p53− Hep3B, ↑ AMPK ↓ PI3K/Akt/mTOR signaling Protection from liver damage and HCC formation | [161] |
SW1736 and HTh-7 thyroid cancer cells (10 µg/mL) | Induction of autophagy ↑ LC3 II/LC3 I ratio ↑ Autophagic vesicles ↑ LC3-puncta structures ↓ Akt/mTOR signaling | [162] | ||
SGC-7901 gastric cancer cells | Induction of autophagy ↑ LC3 II/I ratio ↑ Beclin 1 expression | [163] | ||
Anthocyanins, extracted from black soybean | U2OS osteosarcoma cells (100–300 µg/mL) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3-puncta structures ↑ p-ERK1/2, p-p38 MAPK, p-JNK, p-Akt ↓ p-mTOR ↑ AMPK | [164] | |
Anthocyanins from Pelingo apple | MCF-7 and MDA-MB-231 breast cancer cells (2.5% v/v of Pelingo juice) | Induction of autophagy ↑ LC3 II/I ratio ↑ Autophagic vacuoles ↑ p21 expression ↓ ERK1/2 | [165] | |
Illawarra plum extract | HT-29 colonic cancer cells (100 µg/mL) | Induction of autophagy ↑ Alteration of morphology ↑ Autophagic vacuoles ↑ SIRT1 expression ↑ Nuclear buds, micronuclei, and nucleoplasmic bridges | [166] | |
Cinnamtannin D1 | A549 and H460 NSCLC cells (125–175 μM) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 II expression ↑ ATG5 expression ↓ Akt/mTOR ↑ ERK1/2 | [167] | |
Proanthocyanidin-rich cranberry extract | JHAD1 and OE19 esophageal adenocarcinoma cells (75 μg/mL) | Induction of autophagy ↓ Beclin 1 expression ↑ LC3 II expression ↑ Autophagic vacuoles | [168] | |
Flavanones | ||||
Hesperidin | Male Swiss albino mice i.p. injected with AOM (25 mg/kg, p.o., daily) | Induction of autophagy ↑ Beclin 1 expression ↑ LC3 II expression ↓ PI3K/Akt/GSK-3β and mTOR pathways | [169] | |
Naringin | Male C57BL/6 mice i.p. injected with AOM and DSS (50 and 100 mg/kg, p.o., daily) | Inhibition ER-stress mediated autophagy Inhibition formation of autophagosomes | [170] | |
AGS gastric cancer cells (2 mM) | Induction of autophagy Formation of cytoplasmic vacuoles and autophagosomes ↑ Beclin 1 and LC3 II expression ↓ PI3K/Akt/mTOR pathway ↑ MAPKs | [171] | ||
Pinocembrin | B16-F10 and A375 melanoma cells (50–150 µM) | C57BL/6 mice s.c. implanted into the oxter with B16-F10 cells (50 mg/kg or 75 mg/kg, i.v., daily) | Inhibition of autophagy ↑ LC3 I expression ↓ ATG5 and ATG5-ATG12 expression ↓ Beclin 1 expression ↑ p62 expression ↓ AVOs ↑ PI3K/Akt/mTOR pathway | [172] |
5-Methoxyflavanone | HCT-116 colon cancer cells (40 µM) | Induction of cytoprotective autophagy ↑ Autolysosomes ↑ LC3-puncta structures ↑ LC3 II expression ↑ LC3 I to LC3 II conversion | [173] | |
6-CEPN | SW620 and HCT-116 colon cancer cells (10 µM) | Induction of cytoprotective autophagy ↑ AVOs ↑ MDC-labelled vacuoles ↑ LC3-puncta structures ↑ LC3 II expression | [174] | |
Liquiritin | SGC-7901/DDP cisplatin (DDP)-resistant gastric cancer cells (80 µM + DDP) | BALB/c-nu mice s.c. injected with SGC-7901/DDP cells (15 mg/kg, i.p., daily + DDP) | Induction of autophagy ↑ Beclin 1 expression ↑ LC3 II expression ↓ p62 expression | [175] |
Silibinin | DU145 prostate cancer cells (100 µM + Arsenic) | Induction of autophagy ↑ Autophagic vacuoles ↑ Beclin 1 expression | [176] | |
Isoflavones | ||||
Genistein | A2780 ovarian cancer cells (50–100 µM) | Induction of autophagy ↑ LC3-puncta structures ↓ Akt phosphorylation | [177] | |
MCF-7 breast cancer cells (100 µM) | Induction of autophagy ↑ LC3-puncta structures | [178] | ||
DMBA-induced mammary tumors in Sprague–Dawley rats fed with AIN93G diet supplemented with 500 ppm genistein | Inhibition of autophagy ↓ GRP78, IRE1α, ATF4 and Beclin 1 genes ↑ Sensitivity to tamoxifen | [179] | ||
A549 NSCLC cells (60 µM) | Induction of autophagy ↓ Bcl-xL levels ↑ LC3 II expression ↓ p62 expression Dissociation of Bcl-xL/Beclin 1 proteins | [180] | ||
MIA PaCa-2 pancreatic cancer cells (100 µM) | Nude mice s.c. injected with MIA PaCa-2 cells (1.3 mg, i.p., every 4 days + 5-FU) | Induction of autophagy ↓ Bcl-2 expression ↑ Beclin 1 expression ↑ AVOs ↑ 5-FU anticancer effects | [181] | |
TRAIL-resistant A549 NSCLC cells (10–40 µM) | Inhibition of autophagy ↑ LC3 II expression ↑ p62 expression ↑ TRAIL-induced cell death | [182] | ||
I3C | HT-29 colon cancer cells (40 µM + I3C 300 µM) | Induction of autophagy ↑ LC3 II expression ↓ Akt/mTOR pathway ↓ Maturation of autophagosomes | [183] | |
Puerarin | K562 CML cells (100 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II/I ratio ↑ ATG5 expression | [184] | |
NCI-H441 NSCLC cells (20 µM) | Induction of autophagy ↑ MDC-labelled vacuoles ↑ ATG5 expression ↓ LC3 I expression ↓ Akt/mTOR pathway | [185] | ||
NV-128 | EOC and R182 paclitaxel- and carboplatin-resistant ovarian cancer cells (0.1–10 µM) | Induction of autophagy ↑ LC3 II expression | [186] | |
Furowanin A | HT-29 and SW480 colon cancer cells (2 and 5 µM) | Induction of autophagy ↑ AVOs ↑ LC3 II and Beclin 1 expression ↓ p62 expression ↑ Autophagosomes | [187] | |
Glabridin | Huh7 hepatoma cells (1–100 µM) | Induction of cytoprotective autophagy ↑ AVOs ↑ LC3 II and Beclin 1 expression | [188] | |
Celastrol | HeLa cervical cancer cells, A549 NSCLC cells, PC-3 prostate cancer cells (1.2 µM) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ LC3 II expression | [189] | |
SH-SY5Y neuroblastoma cells (500 nM) | Induction of autophagy ↑ LC3 II/I ratio ↑ Autophagosomes | [190] | ||
Phenoxodiol | KK ovarian clear cell carcinoma cells (0.5–2 µg/mL) | Inhibition of autophagy ↓ ATG7, ATG12, Beclin 1 expression ↑ Sensitivity to cisplatin | [191] | |
Non-Flavonoids | ||||
Coumarins | ||||
Hybrid of 3-benzyl coumarin seco-B-ring derivative and phenylsulfonylfuroxan | A549 NSCLC cells (50 nM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression ↑ LC3 I to LC3 II conversion ↑ Autophagic flux | [192] | |
Hybrid compound of coumarin and phenylsulfonylfuroxan | A549 and H1299 NSCLC cells (200 nM) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ LC3 I to LC3 II conversion | [193] | |
Feroniellin A | A549RT-eto NSCLC cells (0.05–1 mM) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3-puncta structures ↑ Beclin 1 and ATG5 expression ↓ mTOR pathway | [194] | |
Esculetin | HL-60 AML cells (20 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II and Beclin 1 expression ↓ ATG3 and p62 expression | [195] | |
Xanthoxyletin | SCC-1 OSCC cells (5–20 µM) | Induction of autophagy ↑ Autophagosomes ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [196] | |
Osthole | T98G glioblastoma multiforme cells and MOGGCCM anaplastic astrocytoma cells (150–250 µM) | Induction of autophagy ↑ Autophagic cells ↑ Beclin 1 expression | [197] | |
Psoralen and isopsoralen | PC-3 prostate cancer cells (250 µg/mL) | Induction of autophagy ↑ AVOs ↑ LC3 II expression ↓ p62 expression | [198] | |
Geranylated 4-phenylcoumarin | PC-3 and DU145 prostate cancer cells (9 µM) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3-puncta structures ↑ Autophagosomes ↓ p62 expression | [199] | |
Hydroxypyridinone-coumarin | MHCC-97 and HepG2 HCC cells (2 µM) | Induction of autophagy ↑ ATG5, ATG3, Beclin 1 and LC3 II expression ↓ p62 expression ↑ ERK1/2 ↓ Akt | [200] | |
Psoralidin | HepG2 HCC cells (9–26 µM) | Induction of autophagy ↑ Autophagosomes ↑ Beclin 1 and LC3 II expression | [201] | |
MCF-7 breast cancer cells (2.5–10 µM) | Induction of cytoprotective autophagy ↑ Beclin 1, LC3 II and p-ULK1 (Ser317) expression ↓ p62 expression ↓ Akt/mTOR pathway ↑ MDC-labelled vacuoles | [202] | ||
Bergapten | MCF-7 and ZR-75 breast cancer cells (20–50 µM) | Induction of autophagy ↑ Beclin 1, PI3KII, UVRAG, AMBRA ↑ LC3 I to LC3 II conversion ↑ Autophagosomes ↑ pTEN and p38 MAPK/NF-Y pathway ↓ Akt/mTOR pathway | [203] | |
Curcuminoids | ||||
Curcumin | A549 NSCLC cells (5–40 µM) | Induction of autophagy ↑ Autophagic vesicles ↑ MDC-labelled vacuoles ↑ Double membrane-enclosed structures ↑ LC3 II and Beclin 1 expression ↑ LC3 II/I ratio ↓ p62 expression ↓ Akt, mTOR expression | [204,205] | |
A549 NSCLC cells (40 µM) | Induction of autophagy ↑ LC3-puncta structures ↑ AMPK pathway ↑ hST8Sia I, GD | [206] | ||
H1299 and A549 NSCLC cells (10 µM) | Induction of autophagy ↑ Beclin 1 expression ↑ LC3 II/I ratio ↑ Autophagosomes ↓ p-mTOR, p-S6, p-PI3K, p-Akt | [207] | ||
A549 NSCLC cells (40 µM + Galbanic acid) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 II expression ↑ Beclin 1 expression ↓ p-Akt, p-mTOR, p-p70S6K | [208] | ||
H157 and H1299 NSCLC cells (10 µM + Gefitinib) | BALB/c athymic nude mice s.c. injected with H157 or H1299 cells (1 g/kg, p.o., daily + Gefitinib) | Induction of autophagy ↑ LC3-puncta structures ↑ AVOs ↓ SQSTM1
↑ LC3, Beclin 1 ↓ EGR, survivin, Sp1, HDAC1 | [209] | |
PANC1 and BxPC3 pancreatic cancer cells (10–80 µg/mL) | Induction of autophagy ↑ LC3 II expression ↑ Autophagosomes ↑ LC3-puncta structures | [210] | ||
SGC-7901 and BGC-823 gastric cancer cells (10–40 µM) | Induction of autophagy ↑ Beclin 1, ATG5, ATG3 expression ↑ LC3 I to LC3 II conversion ↓ p-mTOR, PI3K, p-Akt | [211] | ||
SGC-7901, BGC-823 and MKN-28 gastric cancer cells (5–20 µM) | Induction of autophagy ↑ AVOs ↑ Beclin 1, ATG7, ATG5-ATG12 expression ↑ LC3 I to LC3 II conversion ↓ p-Akt, p-mTOR, p-p70S6K | [212] | ||
SKOV-3 and A2780 ovarian cancer cells (SKOV-3: 10–40 µM) (A2780: 7.5–30 µM) | Induction of autophagy ↑ AVOs ↑ LC3 I/II ratio ↑ LC3-puncta structures ↑ Beclin 1, ATG3 expression ↓ p-Akt, p-mTOR, p-p70S6K, p-4EBP1 | [213] | ||
SW620 and HCT-116 colon cancer cells (10–30 µM) | Induction of autophagy ↑ LC3 expression ↓ p62 expression ↓ YAP expression | [214] | ||
HCT-116 and HT-29 colon cancer cells (10–30 µM + 5-FU) | BALB/c nu/nu mice s.c. injected with HCT-116 cells (40 mg/kg, i.p., daily + 5-FU) | Induction of autophagy ↓ LC3 II/II ratio, Beclin 1 expression ↑ p62 expression ↓ p-Akt, p-mTOR, p-AMPK, p-ULK1 | [215] | |
HepG2 HCC cells (5–20 µM) | BALB/c nude mice s.c. injected with HepG2 cells (200 mg/kg, i.p., daily) | Induction of autophagy ↑ Beclin 1, LC3 expression ↓ Glypican-3 (GPC3) ↓ Wnt/β-catenin pathway | [216] | |
Sprague Dawley rats (100–200 mg/kg, p.o., daily + TAA) | Induction of autophagy ↑ LC3 II expression ↓ ALT, AST, albumin ↑ Survival | [217] | ||
HeLa cervical cancer cells, HCT-116 colon carcinoma cells, HepG2 HCC cells (40 µM + JLP silencing) | Induction of cytoprotective autophagy ↑ LC3 II expression ↓ Autophagosomes-lysosome fusion and degradation with JLP silencing | [218] | ||
786-O and ACHN RCC cells (5–80 µM) | ↑ LC3 II expression
↑ p-AMPK ↑ GRP78, CHOP expression ↓ ROS production
↓ p-AMPK ↓ GRP78, CHOP expression ↑ ROS production | [219] | ||
MM-B1, H-Meso-1, MM-F1 and murine #40a malignant mesothelioma cells (25 µM) | Induction of autophagy, but autophagic flux blocked ↑ p62/SQSMT1, LC3 I | [220] | ||
TUBO murine Her2/neu+ breast cancer cells (25 μM + CQ) | Immunocompetent or immunocompromised BALB/c mice s.c. injected with TUBO cells (100 mg/kg, p.o., 3 times a week + CQ) | ↓ p62 expression ↑ LC3 II expression
↑ Tumor growth ↑ Autophagosomes in tumor tissues ↓ p62 expression ↓ Foxp3+ T regulatory cells ↑ CD8+ T cells
↓ Tumor growth | [221] | |
CAL-27, SCC-15 and FaDu HNSCC cancer cells (25 μM + Resveratrol) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3 II expression ↑ Autophagosomes | [222] | ||
SUP-B15 Ph+ acute lymphoblastic leukemia cells (30 µM) | Induction of autophagy ↑ RAF/MEK/ERK pathway ↑ Autophagy | [223] | ||
A172 glioblastoma cells (10 µM) | Induction of autophagy ↑ LC3 II expression ↑ LC3-puncta structures ↑ ATG5, ATG12, Beclin 1 expression | [224] | ||
Caki, ACHN and A498 renal carcinoma cells; U87MG glioma cells; MDA-MB-231 breast carcinoma cells (20 µM + PP242) | Induction of autophagy ↓ mTORC2/Akt pathway ↓ Rictor, Akt ↑ Cytosolic Ca2+, MMP, cytosolic pH ↑ Autophagy, Lysophagy, galectin-3 Colocalization of LAMP-1 and p62 ↑ LC3-puncta structures ↑ LC3 II expression ↑ p62 expression | [225] | ||
HCT-116, HT-29, HepG2 and Huh7 gastrointestinal cancer cells (2 µM + Sildenafil) | Induction of autophagy ↓ mTORC1 and mTORC2 activity ↑ Beclin 1 ↑ Autophagosome and autolysosome | [226] | ||
CUR or solid lipid CUR particles (SLCP) | U87MG; mouse, GL261; rat, F98 glioblastoma cells; C6-glioma rat glial tumor cells; N2a cells mouse neuroblastoma cells (25 µM) | Induction of autophagy ↑ ATG5, ATG7, Beclin 1 ↑ LC3A/B-II/LC3A/B-I ratio ↓ Mitophagy markers PINK-1, NIP3L/NIX, BNIP3, HIH-1α ↓ Akt/mTOR pathway ↓ Akt, p-Akt, mTOR and p-mTOR ↓ LAMP-2a ↑ Autophagic vacuoles and membrane blebbing | [227] | |
CUR-LDH | MDA-MB-231 breast cancer cells (25–100 µg/mL + Photodynamic therapy) | ↑ Autophagosomes | [228] | |
Curcumin DMC BDMC | SAS oral cancer cell line (CUR: 30 µM) (DMC, BDMC: 15 µM) | Induction of autophagy ↑ Autophagic vacuoles ↑ MDC-labelled vacuoles ↓ p-mTOR, ↑ AMPKα1, Vps34, ULK1, ATG16L1, ATG5 ↑ LC3, Beclin 1 | [229] | |
Curcumin DMC BDMC TetrahydroCUR | SAS oral cancer cell line + Gefitinib (CUR: 20 µM) (DMC, BDMC: 5 µM) | BALB/c athymic nude mice s.c. injected with SAS cells (30 mg/kg, i.p., every two days + gefitinib) | Induction of autophagy ↑ Cleaved-caspase-3 ↓ MMP ↑ Autophagic vacuoles ↑ ATG5, p62/SQSTM1, ULK1, Vps34 ↑ LC3, Beclin 1
↑ Beclin 1 | [230] |
Chemotherapy-resistant HL60 human leukemia cells | Induction of autophagy ↑ LC3 II expression ↑ p62 expression | [231] | ||
TetrahydroCUR | A549 NSCLC cells (10–130 µM) | Induction of autophagy ↑ AVOs ↑ Beclin 1 expression ↓ mTOR, p-mTOR, p-Akt ↓ p62 expression ↑ LC3 II/I ratio ↑ PI3K | [232] | |
CA-5f | A549, H1299 and H157 NSCLC cells; HUVEC umbilical vein endothelial cells; HepG2 HCC cells; HeLa cervical cancer cells; HEK293 embryonic kidney 293 cells (1–40 µM) | BALB/c nude mice s.c. injected with A549 cells (40 mg/kg, i.v., every two days) | Inhibition of autophagy ↑ SQSTM1 expression ↓ Autophagophores degradation Modulation of cytoskeleton protein, membrane trafficking, vesicles mediated transport
↑ LC3 II expression ↑ SQSTM1 | [233] |
ZYX01 | A549 NSCLC cells | Induction of autophagy ↑ AMPK/ULK1/Beclin 1 pathway ↑ LC3 II/I ratio ↑ Beclin 1 ↓ p62 expression | [234] | |
MOMI-1 | A549 NSCLC cells; MCF-7 breast cancer cells; HepG2 HCC cells (20 µM) | Induction of autophagy ↑ Autophagic vacuoles ↑ MDC-labelled vacuoles ↑ LC3-puncta structures ↓ p62 expression ↑ Beclin 1 ↑ LC3 I to LC3 II conversion | [235] | |
MTH-3 | MDA-MB-231 breast cancer cells (10 µM) | Induction of autophagy ↑ LC3 expression ↑ p62 expression ↑ ATG5, ATG7, ATG12, Beclin 1 | [236] | |
WZ35 | HCCLM3 HCC cells (20 µg/mL) | Induction of autophagy ↑ Autophagic vacuoles Deregulated YAP signaling ↓ LC3 I/II ratio ↓ ATG7, Beclin 1 expression ↑ p62 expression | [237] | |
Phenolic Acids | ||||
Ellagic acid | HOP62 and H1975 lung cancer cells (10–50 µM) | BALB/c nude mice s.c. injected with HOP62 cells (40 mg/kg, i.p., every 2 days) | Induction of autophagy ↑ LC3-positive autophagosomes ↑ LC3 II and ATG5 expression ↓ p62 expression ↑ Activation AMPK ↓ mTORC1 and Akt | [238] |
SKOV-3 ovarian cancer cells (36.6 µM) | Induction of autophagy ↑ LC3 II/I ratio ↑ Beclin 1 and ATG5 expression ↓ p62 expression ↑ Activation AMPK ↓ mTORC1 and Akt | [239] | ||
Punicalagin | U87MG glioma cells (1–30 µg/mL) | Induction of autophagy ↑ LC3 II expression ↓ LC3 I expression ↑ LC3-puncta structures ↑ Activation AMPK and p27 | [240] | |
Grias Nuberthii extract | RKO and SW613-B3 colon cancer cells (20, 30, 50 µg/mL) | Induction of autophagy ↑ Beclin 1 and LC3 II expression ↓ p62 expression | [241] | |
Gallic acid | Cal33 OSCC cells (0.1, 0.5, 1 mg/mL) | Induction of cytoprotective autophagy, but autophagic flux blocked ↑ LC3 I to LC3 II conversion ↑ Beclin 1 and ATG5-ATG12 expression ↑ p62 expression ↓ Autolysosome formation | [242] | |
Paeonol | A2780 and SKOV-3 ovarian cancer cells (0.6–1.2 mM) | BALB/c nude mice (nu/nu) s.c injected with A2780 cells (40 mg/kg, i.p., every 2 days) | Induction of cytoprotective autophagy ↑ LC3 I to LC3 II conversion ↑ Autophagosomes ↓ p62 expression ↓ Akt/mTOR pathway | [243] |
PGG | DU145, PC-3, TRAMP-C2 prostate cancer cells (25–75 µM) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ LC3 II expression ↓ S6K and 4EBP1 ↑ Akt activation | [244] | |
Corilagin | SGC-7901 and BGC-823 gastric cancer cells (10–30 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression ↑ Autophagosomes | [245] | |
CAPE + EECP | MDA-MB-231 breast cancer cells (CAPE: 25 µg/mL + EECP: 25–100 µg/mL) | Induction of autophagy ↑ LC3 II expression ↓ p62 expression | [246] | |
CAPE | C6 glioma cells (10 µM) | Induction of cytoprotective autophagy ↑ LC3 II/I ratio ↑ Autophagosomes ↑ AMPK activation | [247] | |
Decyl caffeic acid | HCT-116 colorectal cancer cells (40 µM) | Induction of cytoprotective autophagy ↑ ATG3, ATG16, Beclin 1 and LC3 I/II expression | [248] | |
Artepillin C | CWR22Rv1 prostate cancer (50–100 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression | [249] | |
Cinnamomum cassia extracts | SASVO3 oral cancer cells (50–100 µg/mL) | Induction of cytoprotective autophagy ↑ AVOs ↑ LC3 I, LC3 II, ATG14, rubicon and p62 expression ↓ PI3K/Akt/mTOR pathway | [250] | |
Ferulic acid | HeLa and Caski cervical cancer cells (2.0–4.0 mM) | Inhibition of autophagy ↓ LC3 II, Beclin 1, ATG5-ATG12 expression | [251] | |
Tributyltin (IV) ferulate | HCT-116, HT-29, Caco-2 colon cancer cells (400 nM) | Induction of autophagy ↑ MDC-labelled vacuoles ↑ LC3 II and p62 expression | [252] | |
p-coumaric acid | N2a neuroblastoma cells (150–200 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression | [253] | |
Ganoderma lucidum methanolic extract | AGS gastric cancer cells (66.6 and 133.2 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression ↓ p62 expression | [254] | |
Lignans | ||||
Honokiol | B16-F10, SKMEL-28 melanoma cancer cells (30–40 µM) | Induction of autophagy Formation of autophagosomes ↑ LC3 II expression and cytoplasmic accumulation ↓ Akt/mTOR pathway and Notch signaling | [255,256] | |
MG-63 osteosarcoma cells (10–20 µg/mL) | Induction of autophagy ↑ LC3 II expression ↓ Akt/mTOR pathway | [257] | ||
ARO, WRO, SW579 thyroid cancer cells (20–60 µM) | BALB/cAnN.Cg-Foxn1nu/CrlNarl nude mice s.c. injected with ARO cells (5 or 15 mg/kg, p.o., every 3 days) | Induction of autophagy ↑ LC3 II expression ↓ p62 expression | [258] | |
Neuro-2a and NB41A3 neuroblastoma cells (50 µM) | Induction of autophagy ↑ AVOs ↑ LC3 II/I ratio | [259] | ||
Drug sensitive (U87MG, murine GL261) and resistant (U87-MR-R9) glioma cells (40 µM + TMZ) | Induction of autophagy ↑ Autophagic cells percentage | [260] | ||
PC-3, LNCaP, murine Myc-CaP prostate cancer cells (40 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression Formation of autophagic vacuoles ↑ LC3-puncta structures | [261] | ||
OC2 and OCSL OSCC cells (20–40 µM) | BALB/cAnN.Cg-Foxn1nu/CrlNarl nude mice s.c. injected with SAS cells (5 and 15 mg/kg, p.o., twice a week) | Induction of autophagy ↑ LC3 II expression | [262] | |
Honokiol + Magnolol | U87MG and LN229 glioma cells (40 µM, each) | Induction of cytoprotective autophagy ↑ LC3 II expression | [263] | |
Vitexin 6 | T-47D breast cancer cells and RKO colon cancer cells (5–20 µM) | Induction of autophagy Formation of autophagosomes ↑ LC3 II conversion ↑ LC3 II and Beclin 1 expression | [264] | |
Licarin A | A549 and NCI-H23 NSCLC cells (10–25 µM) | Induction of autophagy ↑ AVOs ↑ Beclin 1, LC3 II mRNA levels ↓ p62 levels | [265] | |
Trachelogenin | HCT-116 colon cancer cells (5–10 µM) | Induction of autophagy ↑ AVOs ↑ Beclin 1 ↑ LC3 I to LC3 II conversion | [266] | |
Magnolin | HCT-116 and SW480 colon cancer cells (10–40 µM) | BALB/c athymic nude mice s.c. injected with HCT-116 cells (20 mg/kg, i.p., daily) | Induction of autophagy ↑ LC3 II expression ↓ p62 expression Accumulation of double membrane vesicles ↑ LC3-puncta structures | [267] |
Justicidin A | HT-29 colon cancer cells (0.5–1.5 µM) | NOD-SCID mice s.c. injected with HT-29 cells (6.2 mg, p.o., daily) | Induction of autophagy ↑ LC3 I to LC3 II conversion ↑ LC3 II expression ↑ AVOs ↑ LC3-puncta structures ↓ p62 expression ↓ p-mTOR, p-p70S6K expression ↑ Beclin 1, ATG5-ATG12 expression | [268] |
Pinoresinol | SKOV-3 ovarian cancer cells (10–40 µM) | Mice s.c. injected with SKOV-3 cells (40 mg/kg, i.p., thrice a week) | Induction of autophagy Formation of autophagic vesicles ↑ LC3 II expression ↑ Beclin 1 expression ↓ p62 expression | [269] |
Sesamin | HeLa cervical cancer cells (50 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression ↑ Beclin 1 expression | [270] | |
HT-29 and LS180 colon cancer cells (50 µM) | Induction of autophagy Formation of double membrane vacuoles ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion ↑ MDC-labelled vacuoles | [271] | ||
Magnolol | H460, A549 and NCI-H1299 NSCLC cells (A549: 80 µM) (A549 and NCI-H1299: 10–20 µM) | Induction of autophagy Formation of autophagosomes ↑ MDC-labeled vacuoles ↑ ATG5, ATG12 expression ↑ LC3 II/I ratio ↓ p62 expression ↓ Akt/mTOR pathway | [272,273] | |
SGC-7901 human gastric adenocarcinoma cells (40–80 µM) | Induction of autophagy ↑ AVOs | [274] | ||
Arctigenin | MCF-7 breast cancer cells (1–200 µM) | Induction of autophagy ↑ LC3 II expression ↑ LC3 II/I ratio ↓ mTOR pathway | [275] | |
R-SW480, R-SW620 cisplatin resistant colorectal cancer (100 µM + Cisplatin) | Induction of autophagy ↑ LC3 II expression ↑ p65 expression ↓ LC3 I expression | [276] | ||
HepG2 HCC cells (1.25–10 µM) | Inhibition of autophagy ↑ LC3 II expression ↑ Beclin 1 phosphorylation ↑ p62 levels | [277] | ||
DFS | DU145 prostate cancer cells and SW480 colon cancer cells (10 µM) | Induction of cytoprotective autophagy ↑ LC3 II levels ↑ Autophagosomes and autolysosomes | [278] | |
Stilbenes | ||||
Resveratrol | HL-60 AML cells (12.5–100 μM) | Induction of autophagy ↑ LC3 II, ATG5 and Beclin 1 expression ↑ LKB1/AMPK activation ↓ PI3K/Akt/mTOR pathway | [279] | |
K562 CML cells (50 μM) | Induction of autophagy ↑ AMPK activation ↓ mTOR pathway ↑ LC3 II and ATG3 expression ↑ p62 expression | [280] | ||
HT-29 and COLO201 colon cancer cells (HT-29: 150 μM) (COLO201: 75 μM) | Induction of autophagy ↑ LC3 II expression ↑ Autophagic vacuoles ↑ LC3-puncta structures | [281] | ||
HK-2 and Ketr-3 renal carcinoma cells (12.5–100 μM) | Induction of autophagy ↑AMPK activation ↓ mTOR phosphorylation ↑ LC3, ATG5, ATG7 expression | [282] | ||
MHCC-97 HCC cells (20–100 μM) | Induction of autophagy ↑ LC3 II/I ratio ↑ Beclin 1 expression ↓ p62 expression ↑ LC3-puncta structures ↓ p-Akt/Akt ratio | [283] | ||
C33A, CaLo, and HeLa cervical cancer cells (30–50 μM) | Induction of autophagy ↑ Lysosomal permeability ↑ Lysosomal swelling and degranulation ↑ Vacuoles and autophagosomes | [284] | ||
CAR cisplatin-resistant oral carcinoma cells (50 μM) | Induction of autophagy ↑ AVOs ↑ MDC-labeled vacuoles ↑ LC3-puncta structures ↑ AMPK activation ↓ Akt activation ↑ ATG5, ATG7, ATG12, ATG14, ATG16L1, Beclin 1 and LC3 II expression | [285] | ||
U373 glioma cells (100 μM) | Induction of autophagy ↑ LC3-labeled vesicles | [286] | ||
U87 glioma cells (30 μM) | Induction of cytoprotective autophagy ↑ Autophagosomes ↑ ATG5, Beclin 1 and LC3 II expression ↓ Akt and p70S6K activation | [287] | ||
U251 glioma cells (150 μM) | Induction of cytoprotective autophagy ↑ MDC-labeled vacuoles ↑ LC3-puncta structures ↑ LC3 II and Beclin 1 expression | [288] | ||
OVCAR-3 and CAOV-3 ovarian cancer cells (30μM) | Induction of autophagy ↑ LC3 II and ATG5 expression | [289] | ||
SKOV-3 ovarian cancer cells (25 μM) | Induction of cytoprotective autophagy ↑ LC3 II and Beclin 1 expression ↑ MDC-labeled vacuoles | [290] | ||
OVCAR-3 and CAOV-3 ovarian cancer cells (120 μM) | Induction of autophagy ↑ LC3 II and Beclin 1 expression ↑ LC3-labeled vesicles ↑ Autophagosomes ↓ STAT3 activation | [291] | ||
Female nu/nu mice injected i.p. with GFP-labeled A2780 ovarian carcinoma cells (160 mg/kg, i.p., daily) | Induction of autophagy ↑ Autophagosomes | [292] | ||
Ishikawa endometrial carcinoma cells (20 μM) | Induction of cytoprotective autophagy ↑ LC3 II expression ↑ Autophagosomes ↑ p-ERK and p-AMPKα | [293] | ||
A549 NSCLC cells (50 μM) | Induction of autophagy ↑ p62 degradation ↑ LC3 II expression ↑ MDC-labeled vacuoles | [294] | ||
A549 and H1299 NSCLC cells (200 μM) | Induction of cytoprotective autophagy ↑ Beclin 1 expression ↑ LC3 II/I ratio ↓ p62 expression ↑ SIRT 1 expression ↓ Akt/mTOR pathway ↑ p38 MAPK activation | [295] | ||
PC9 NSCLC cells (40 μΜ + Gefitinib) | Induction of cytoprotective autophagy ↑ LC3B II expression ↑ MDC-labelled vacuoles | [296] | ||
A549 NSCLC cells (2.5 μM + Cisplatin) | Induction of autophagy ↑ Autophagosomes ↑ LC3 II expression ↓ p62 expression ↓ p-Akt ↑ LC3-puncta structures ↑ Autophagosomes | [297] | ||
MSTO-211H and H-2452 malignant mesothelioma cells (30 μM + Cisplatin) | Induction of cytoprotective autophagy ↑ LC3 A and Beclin 1 expression | [298] | ||
EC109 and EC9706 squamous esophageal carcinoma cells (10–150 μM) | Induction of cytoprotective autophagy ↑ MDC-labelled vacuoles ↑ AVOs ↑ LC3 II, ATG5 and Beclin 1 expression ↑ Autophagosomes | [299] | ||
B16 melanoma cells (25–100 μM) | Induction of cytoprotective autophagy ↑ LC3 II and Beclin 1 expression ↓ Akt/mTOR pathway | [300] | ||
MCF-7 breast cancer cells (64 μM) | Induction of autophagy ↑ LC3-puncta structure ↑ LC3 II expression ATG7, Beclin 1 and Vps34 expression unchanged ↓ Akt/mTOR pathway | [301] | ||
MCF-7 and MDA-MB-231 breast cancer cells (100 μM + Rapamycin) | Inhibition of rapamycin-induced autophagy ↓ LC3 II expression ↑ p62 expression ↓ Akt activation | [302] | ||
MCF-7 and MDA-MB-231 breast cancer cells (MCF-7: 84.6 μM + DOX) (MDA-MB-231: 108 μM + DOX) | Inhibition of DOX-induced autophagy ↓ LC3B expression ↓ Beclin 1 expression ↓ Akt activation | [303] | ||
MDA-MB-231 breast cancer cells (72 μM + Salinomycin) | Inhibition of salinomycin-induced autophagy ↓ LC3 expression ↓ Beclin 1 expression | [304] | ||
A431 epidermoid carcinoma cells (50 μM) | No autolysosome formation ↑ LAMP-2 expression ↑ LC3 II expression ↓ Rictor expression | [305] | ||
Pterostilbene | HL-60 AML cells | Induction of autophagy ↑ LC3 II expression ↑ LC3-puncta structures Accumulation autophagic vacuoles Reduction in autophagic degradation | [306] | |
Bcap-37 and MCF-7 breast cancer cells (50 μM) | Induction of cytoprotective autophagy ↑ LC3B II expression ↑ Autophagosomes | [307] | ||
CAR cisplatin-resistant human oral cancer cells (50 and 75 μM) | Induction of autophagy ↑ AVOs ↑ MDC-labelled vacuoles ↑ ATG5, ATG7, ATG12, Beclin 1 and LC3 II expression ↓ p-Akt | [308] | ||
Xanthones | ||||
α-Mangostin | GBM8401 and DBTRG-05MG glioblastoma cells (2.5–10 µM) | BALB/cA-ν (ν/ν) nude mice s.c. injected with GBM8401 cells (2 mg/kg, i.p., daily) | Induction of autophagy ↑ AVOs ↑ MDC-labelled vacuoles ↑ Autophagosomes ↑ LC3-puncta structures ↑ AMPK pathway ↓ mTORC1 activity | [309] |
ICR mice treated topically with DMBA/TPA (5 and 20 mg/kg, i.p., daily) | Induction of autophagy ↑ LC3, LC3 II, Beclin 1 expression ↓ LC3 I and p62 expression ↓ PI3K/Akt/mTOR pathway | [310] | ||
K562, KBM5 and KBM5-T135I CML cells (5–20 µM) | Induction of cytoprotective autophagy ↑ LC3 II expression ↑ Autophagic vacuoles | [311] | ||
Gambogic acid | K562 CML cells (0.5–2 µM) | Induction of autophagy ↑ Autophagic vacuoles ↑ LC3 II and Beclin 1 expression ↓ p62 expression | [312] | |
NCI-H441 NSCLC cells | Induction of autophagy ↑ Beclin 1 expression ↑ LC3 I to LC3 II conversion ↑ Autophagosomes | [313] | ||
TE13 esophageal cancer cells (0.25–1 µM) | Induction of autophagy, but autophagic flux blocked ↑ LC3 II expression ↑ Autophagosomes ↓ Akt/mTOR pathway | [314] | ||
HCT-116 and SW260 colon cancer cells (0.25–1.5 µM) | BALB/c mice s.c. injected with C26 cells (8 mg/kg, i.p., daily) | Induction of cytoprotective autophagy ↑ Autophagic vacuoles ↑ AVOs ↑ LC3 I to LC3 II conversion ↑ Beclin 1, ATG7, ATG5-ATG12 expression ↓ p62 expression ↓ Akt/mTOR pathway | [315] | |
Gambogenic acid | H1975, H460 lung cancer cells (1.25–25 µM) | Induction of autophagy ↑ Autophagosomes ↑ LC3-puncta structures ↑ LC3 II expression ↑ GSK3β activation ↓ Akt/mTOR pathway | [316] | |
Isogambogenic acid | A549 NSCLC cells and HeLa cervical cancer cells (1.5–12 µM) | BALB/cA nude mice s.c. injected with A549 cells (16 mg/kg, i.v., twice a week) | Induction of autophagy, but autophagic flux blocked ↑ Autophagic vacuoles ↑ LC3 II and Beclin 1 expression ↓ p70S6K phosphorylation Inhibition degradation p62 Inhibition acidification of vacuoles | [317] |
Gartanin | Hep3B, HepG2, Huh7 HCC cells (10–40 µM) | Induction of cytoprotective autophagy ↑ AVOs ↑ LC3 I to LC3 II conversion ↑ LC3-puncta structures ↑ Autophagosomes and autolysosomes ↓ p62 expression | [318] | |
T24 and RT4 urinary bladder cancer cells (10–25 µM) | Induction of autophagy ↑ LC3-puncta structures ↑ Autophagosomes ↑ LC3 I to LC3 II conversion ↓ p70S6K and 4E-BP1 | [319] | ||
T98G glioma cells (10 µM) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 II and Beclin 1 expression ↓ p62 expression ↓ PI3K/Akt/mTOR pathway | [320] | ||
22Rv1 and PC-3 prostate cancer cells (6–24 µM) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 II expression | [321] | ||
Formoxanthone C | MDR A549RT-eto NSCLC cells (20 µg/mL) | Induction of autophagy ↑ Autophagic vacuoles ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion ↑ Beclin 1 expression ↓ p-mTOR levels ↑ Sensitivity to etoposide | [322] | |
Mangiferin | Gemcitabine-resistant Mia-PaCa2 pancreatic carcinoma cells (5–20 µM) | Induction of autophagy ↑ LC3 II and Beclin 1 expression | [323] | |
Gentiana dinarica extract and norswertianin | U251 glioblastoma cells (Extract: 50 µg/mL; noswertianin 40 µM) | Induction of autophagy ↑ AVOs ↑ LC3 I to LC3 II conversion ↓ p62 expression ↓ Akt/mTOR pathway | [324] | |
Xanthone V1 | HeLa cervical cancer cells (10–20 µM) | Induction of autophagy ↑ LC3-puncta structures ↑ LC3 I to LC3 II conversion ↓ p62 expression | [325] | |
Cudraxanthone D | Ca9-22 and SCC25 OSCC cells (50 µM) | Inhibition of autophagy ↓ Autophagic vacuoles | [326] |
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Benvenuto, M.; Albonici, L.; Focaccetti, C.; Ciuffa, S.; Fazi, S.; Cifaldi, L.; Miele, M.T.; De Maio, F.; Tresoldi, I.; Manzari, V.; et al. Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies. Int. J. Mol. Sci. 2020, 21, 6635. https://doi.org/10.3390/ijms21186635
Benvenuto M, Albonici L, Focaccetti C, Ciuffa S, Fazi S, Cifaldi L, Miele MT, De Maio F, Tresoldi I, Manzari V, et al. Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies. International Journal of Molecular Sciences. 2020; 21(18):6635. https://doi.org/10.3390/ijms21186635
Chicago/Turabian StyleBenvenuto, Monica, Loredana Albonici, Chiara Focaccetti, Sara Ciuffa, Sara Fazi, Loredana Cifaldi, Martino Tony Miele, Fernando De Maio, Ilaria Tresoldi, Vittorio Manzari, and et al. 2020. "Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies" International Journal of Molecular Sciences 21, no. 18: 6635. https://doi.org/10.3390/ijms21186635
APA StyleBenvenuto, M., Albonici, L., Focaccetti, C., Ciuffa, S., Fazi, S., Cifaldi, L., Miele, M. T., De Maio, F., Tresoldi, I., Manzari, V., Modesti, A., Masuelli, L., & Bei, R. (2020). Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies. International Journal of Molecular Sciences, 21(18), 6635. https://doi.org/10.3390/ijms21186635