Table 4.

The effect of melatonin on autophagy machinery in recently reported findings

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]