Table 2.
Anticancer activities of melatonin against different cancer types.
| Cancer Type | Study Model | Dose of Melatonin | Main Effects of Melatonin and Outcomes | Reference |
|---|---|---|---|---|
| Gastric cancer | AGS and SGC-7901 cell lines mice |
1 mΜ, 2 mΜ, 3 mΜ melatonin 50 mg/kg melatonin |
inhibited cell proliferation via the activation of the IRE/JNK/Beclin1 signaling induced the expression of apoptotic and autophagy-related proteins |
[214] |
| SGC7901 cell line | 10−4 M melatonin | affected the expression of differentiation relevant factors; the gene expression of endocan was significantly increased and the activity of lactate dehydrogenase and phosphatase was downregulated | [215] | |
| SGC7901 and BGC823 cell lines | 10−4 M melatonin | decreased the motility and migration distance, remodeled cells tight junctions, and increased cells adhesion | [216] | |
| AGS and MGC803 human gastric cell lines | 3 mM melatonin | induced apoptosis by upregulating the apoptosis related proteins; Caspase 3, Caspase 9, and downregulating the phosphorylation and expression of upstream regulators MDM2 and AKT | [217] | |
| SGC7901 gastric cancer cells | 2 mM melatonin | inhibited migration, reduced viability, and induced apoptosis upregulated the expression of phosphorylated (p) p38 and c Jun N terminal kinase (p JNK) protein, and downregulated the expression of nucleic p65 |
[95] | |
| Mice Murine foregastric carcinoma (MFC) cells |
0, 25, 50 and 100 mg/kg melatonin 0, 2, 4, 6, 8 and 10 mM melatonin |
inhibited cells proliferation and decreased the tumor volume increased IL-2, IL-10, and IFN-γ expression decreased IL-6 level |
[218] | |
| Glioblastoma | Glioblastoma cell lines (U251 and T98G) | 0.1–1000 μM melatonin | Reduced cell viability and self-renewal of glioblastoma cells through blocking EZH2-NOTCH1 signaling axis. | [164] |
| U87 MG and A172 cell lines | 1 mM melatonin | induced autophagy increased the levels of LC3 II, and Beclin 1 upregulation of Bcl-2, the key initiator of autophagy enhanced the apoptosis in glioblastoma cells |
[165] |
|
| U251 and U87 glioblastoma cells | 1 nM, 1 mM melatonin | blocked the expression of HIF-1α protein and inhibited the expression of vascular endothelial growth factor and matrix metalloproteinase 2 (MMP-2) under hypoxia | [166] |
|
| Human normal neural stem cells hNSC.100 | 1 μM, 100 μM, 1 mM melatonin | inhibited the proliferation of glioblastoma initiating cells, decreased the clonogenic and self-renewal ability, and downregulated stem cell markers including the transcription factors sox2 oct3/4, nanog, and the transmembrane glycoprotein CD133 decreases the expression levels of de mRNA of these markers |
[167] |
|
| Prostate cancer | Xenografted LNCaP in mice | 1 mg/Kg melatonin | density reduction in the xenograft micro-vessels (lower angiogenesis), and decreased the growth rate downregulated the Ki67 expression, increased the HIF-1α expression, and enhanced phosphorylation of Akt |
[144] |
| Prostate cancer cell line PC-3 cells | 1 mM melatonin | upregulated miRNA3195 and miRNA 374b under hypoxia decreased the mRNA expression of angiogenesis related genes including HIF-1α, HIF-2α and VEGF at mRNA level under hypoxia | [68] | |
| LNCaP and PC-3 prostate cancer cell lines | 1 mM melatonin | increased cell toxicity caused by hrTNF-alpha and NF-related apoptosis-inducing ligand (TRAIL) without affecting the action of docetaxel, doxorubicin, or etoposide induced phenotypic changes, and neuroendocrine differentiation | [142] | |
| Lung cancer | CL1-5 and A549cell lines |
0.1, 0.3, and 1 mM melatonin | reduced the expression of CD133 in lung cancer cells inhibited PLC, β-catenin, ERK/p38, and Twist signaling pathways to suppress lung cancer stemness |
[177] |
| CL1-0, CL1-5 and A549 cell lines male SCID mice |
0.1, 0.3, or 1 mM melatonin | reduced the lung cancer metastasis reversed the phenotype of epithelial–mesenchymal through twist inhibited Twist/Twist1 expression via MT1 receptor, p38/ERK PLC, and β-catenin signaling cascades |
[219] | |
| SK-LU-1 cell line with PBMC | 1 nm, 1 μm and 1 mM melatonin | increased apoptosis and oxidative stress via reduction in GSH, and increased cell cycle arrest | [220] | |
| Ovarian cancer | SKOV3 ovarian cancer cells | 3.4 mM melatonin | inhibited proliferation decreased the expression of the proliferation marker Ki67 reduced the ZEB1, ZEB2, vimentin, and snail expression increased E-cadherin decreased the expression of matrix metalloproteinase 9 (MMP9) |
[83] |
| OVCAR-429 and PA-1 cell lines | 0.4, 0.6, and 0.8 mM melatonin | downregulated CDK 2 and 4 which lead to accumulation of OVCAR-429 and PA-1 cells the G1 phase | [187] | |
| Rats | 200 μg/100 g bw/day | decreased the expression levels of proteins involved in important metabolic processes which are associated with energy generation, mitochondrial processes, antigen presenting and processing, hypoxia, endoplasmic reticulum stress, and cancer-associated proteoglycans overexpression of fatty acids binding proteins, ATP synthase subunit β, and heat shock protein |
[188] | |
| Colorectal cancer | HCT116 cell line (p53 wild type) | 1, 10, 100 μM melatonin | decreased plasma MT1, and increased the nuclear receptor, RORα induced apoptosis and autophagic process decreased cells population in S-phase decreased Trichostatin A-associated cardiotoxicity via inhibition of A- and E-type cyclins, and upregulation of p16 and p-p21 expression promoted G1 phase arrest |
[196] |
| RKO cell line | 1, 2, and 3 mM melatonin | downregulated the levels of Rho-associated protein kinase 2 (ROCK2), p-myosin light chains (p-MLC), and phospho (p)-myosin phosphatase targeting subunit 1 (p-MYPT1) expression increased occluding and ZO-1 expression decreased the levels of p38 phosphorylation supp-ressed the migration of RKO cells |
[197] | |
| Oral cancer | SCC9 and SCC25 cells | 1 mM melatonin | decreased cell viability in both cell lines inhibited the expression of the genes VEGF and HIF-1α under hypoxia and the expression of the gene ROCK-1 in SCC9 cells |
[141] |
| SAS and SCC9 oral cancer cell lines Vincristine (VCR)-resistant oral cancer cells; SASV32, SASV16, SCC9V16, and SCC9V32. |
0.5–2 mM melatonin. | promoted the autophagy and the apoptosis of VCR-resistant oral cancer cells via p38, AKT, and c-Jun N-terminal kinase (JNK) inhibited ATP-binding cassette B1 and 4 induced apoptosis and decreased the drug resistance in VCR-resistant oral cancer cells via increasing the expression of microRNAs |
[204] | |
| Liver cancer | HepG2 hepatocarcinoma cell line | 1 mM melatonin | decreased the cell viability and downregulated the expression of proangiogenic proteins VEGF and HIF-1α under hypoxia and in normal state reduced the cell migration and invasion |
[207] |
| HepG2 hepatocarcinoma cell line | 10−9, 10−7, 10−5 and 10−3 mol/L melatonin | enhanced apoptosis in HepG2 under ER stress via selective blocking of activating transcription factor 6 (ATF-6) inhibition of cyclooxygenase-2 (COX-2) expression, and decreasing Bcl-2/Bax ratio |
[208] | |
| Renal cancer | A498, 786-O, Achn, Caki-1, and Caki-2 cells. Mice |
0.5, 1, and 2 mM melatonin 200 mg/kg melatonin |
modulated ADAMTS1 independently of the MT1 receptor, affecting invasion and growth ability induced microRNA -181d and microRNA -let-7f targeting the non-3′-UTR and 3’-UTR of ADAMTS1 to inhibit its expression and reduce the invasive in renal cancer cells |
[128] |