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Table 4 The effect of melatonin on autophagy machinery in recently reported findings

From: An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress

Cancer

Melatonin dose/concentration

Autophagy-related targets

Effect on autophagy

Key findings

Model

Cell line

Refs.

Lung, liver and cervical cancer

2 mM

LC3

Activate

Induced apoptosis by ROS generation and JNK activation

In vitro

HepG2, A549, HeLa

[124]

Glioblastoma

1 mM

Beclin 1, LC3-II

Activate

Autophagy disruption stimulated the melatonin-mediated apoptosis in cancer cells

In vitro

A172, U87-MG

[97]

Uterine leiomyoma

25 mg/kg

0.1, 0.5, 1, 1.5, 2 mM

Beclin1 and LC3

Activate

Reduced tumor growth and proliferation

In vivo, in vitro

ELT3 cells, orthotopic uterine leiomyoma mouse model

[192]

Hepatocellular carcinoma

10−5_ 10–3 M

PERK-ATF4-Beclin1 pathway

Inhibit

enhanced HCC sensitivity to sorafenib through suppressing autophagy

Human

-

[76]

Colorectal cancer

10 μM

LC3-II

Activate

Induced interplay of apoptosis, autophagy, and senescence

In vitro

HCT116

[171]

Clear cell renal cell carcinoma

200 mg/kg

0.5, 1, 2 μM

PGC1A, UCP1, LC3‐II

Activate

Melatonin/PGC1A/UCP1 promoted tumor slimming and repressed tumor progression through initiating autophagy and lipid browning

In vivo, in vitro

HK2, 786‐O, A498, Caki‐1, and ACHN cells

Mice

[95]

Neuroblastoma

0.1‐ 10 nM

40‐80 mg/kg

LC3II

Activate

Promoted cancer cell differentiation through activation of hyaluronan synthase 3-mediated mitophagy

In vivo, in vitro

N2a

N2a‐allografted nude mice

[193]

Head and neck squamous cell carcinoma

0.1, 0.5, 1, 1.5 mM

ATG12-ATG5

Activate

Induced intracellular ROS

In vitro

Cal-27, SCC-9

[93]

Hepatocellular carcinoma

1 mM

mTOR, Beclin-1

Activate

Decreased cisplatin-mediated cell death by a counter-balance between the roles of apoptotic- and autophagy-related proteins

In vitro

HepG2

[101]

Hepatocellular carcinoma

2 mM

Beclin-1, p62, LC3II, LAMP-2

Activate

Ceramide metabolism regulated apoptotic and autophagy cell death mediated by melatonin

In vitro

HepG2

[96]

Neuroblastoma

1 μM

Beclin‐1, LC3‐II

Activate

Enhanced autophagic activity by the SIRT1 signaling

In vitro

SH‐SY5Y

[194]

Gastric cancer

10−4 M

LC3

Activate

Hyperbaric oxygen sensitized cancer cells to melatonin-mediated apoptosis

In vitro

SGC7901

[151]

Colon cancer

1 mg/kg

Beclin-1, LC3B-II/LC3B-I ratio, p62

Inhibit

Decreased autophagy by improving oxidative stress and inflammation

In vivo

Male Swiss Albino mice

[99]

Glioblastoma

1 mM

LC3, Beclin-1

Activate

Inhibited tumor bulk proliferation, and enhanced chemotherapy effects

In vitro

Glioblastoma-initiating cells

[195]

Oral cancer

0.5–2 mM

LC3-II

Activate

Decreased drug resistance, and induced autophagy and apoptosis

In vitro

SAS, SCC9, SASV16, SASV32, SCC9V16, SCC9V32

[139]

Gastric cancer

50 mg/kg

1, 2, 3 mM

p62, Beclin-1, LC3A/B-II

Activate

Melatonin-mediated inhibition of cancer cell proliferation is induced by the IRE/JNK/Beclin1 signaling activation

In vivo, in vitro

AGS, SGC-7901

Male BALB/c nude mice

[77]

Hepatocellular carcinoma

10, 20 mg/kg

100 μM

Beclin-1, LC3-I/LC3-II

Activate

Induced protective autophagy preventing hepatoma cells from undergoing apoptosis

In vitro, in vivo

H22

[196]

Insulinoma

100 μM

LC3II

Activate

Melatonin-induced insulin synthesis involved autophagy and EDC3 protein in rat insulinoma cells and subsequently resulted in a resuction in intracellular production of insulin

In vitro

INS-1E

[72]

Chriocarcinoma

1 mM

LC3B

Inhibit

Modulated autophagy and the Nrf2 pathway in normal vs. tumor trophoblast cells, being cytoprotective in normal cells whilst enhancing apoptosis in tumoral trophoblast cells

In vitro

BeWo

[197]

Cervical cancer

1 mM

JNK/Parkin

Inhibit

Sensitized cancer cells to cisplatin-mediated apoptosis by suppression of JNK/Parkin/mitophagy pathways

In vitro

HeLa

[100]

Head and neck squamous cell carcinoma

0.1, 0.5 or 1 mM

300 mg/kg

LC3-II, Nix

Activate

Enhanced ROS production, increased apoptosis and mitophagy, and could be used as an adjuvant agent with rapamycin

In vitro, in vivo

Cal-27, SCC-9

Harlan Sprague–Dawley mice

[94]

Tongue squamous cell carcinoma

0, 0.5, 1, 2 mM

100 mg/kg

LC3, ATG7

Activate

Suppression of MT2-TFE3-dependent autophagy enhanced melatonin-mediated apoptosis

In vitro, in vivo

Cal27, SCC9

Male athymic nude mice

[98]