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Table 5 Anticancer effects of melatonin by apoptosis induction in experimental investigations

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 Apoptosis-related targets Key findings Model Cell line Refs.
Oral cancer 0.5–2 mM caspase-3, caspase-9, PARP Decreased drug resistance, and induced autophagy and apoptosis In vitro SCC9V32, SCC9V16, SASV32, SASV16,
SAS, SCC9
[139]
Lung cancer
Hepatocellular carcinoma
Cervical cancer
2 mM caspase-3, PARP, Bax, Bcl-2 Decreased cell viability and increased LDH release In vitro Hela
A549
HepG2
[124]
Glioblastoma 1 mM Bax, Bcl-2 Induced apoptosis and autophagy In vitro A172
U87-MG
[97]
Colorectal cancer 0.5, 1 mM caspase-3, PARP, NEDD9, SOX9, Bcl-xL, SOX10 Enhanced apoptosis through miR-25-5p induced NEDD9 suppression in cancer cells In vitro CCD-18Co, HT29, SW480, HCT116 [121]
Breast cancer 3.5–20 mM
2 mg/kg
caspase-3 Repressed drug resistance through apoptosis induction and angiogenesis inhibition In vitro, in vivo EMT6/CPR, EMT6/VCR/R [140]
Lung cancer 2, 4, 6 mM HDAC9 HDAC9 knockdown increased the anticancer potentials of melatonin In vitro, in vivo A549, H838, H1299, and Calu-1 [118]
Ehrlich
carcinoma
20 mg/kg Bcl‐2, caspase-3, caspase-9, Inhibited the proliferation and growth of tumor via inducing apoptosis and through suppressing tumor vascularization In vivo EAC [141]
Head and neck squamous cell carcinoma 0.1, 0.5, 1, and 1.5 mM Bax, Bcl-2 Potentiated the cytotoxic impacts of radiotherapy and CDDP, and induced intracellular ROS leading to mitochondria-induced autophagy and apoptosis In vitro SCC-9, Cal-27 [93]
Hepatocellular carcinoma 20 mg/kg Caspase-3, Bax, Bcl-2, survivin Fostered the survival and therapeutic potential of MSCs in HCC, by inhibition of oxidative stress and inflammation as well as apoptosis induction In vivo - [120]
Cervical cancer 10 μM CaMKII/Parkin/mitophagy, caspase-3, caspase-9 Enhanced TNF-α-mediated cervical cancer cells mitochondrial apoptosis In vitro HeLa [119]
Gastric cancer 3 mmol/L Caspase 9, Caspase 3, AKT, MDM2 Promoted apoptosis through downregulation of MDM2and AKT In vitro AGS, MGC803 [112]
Melanoma 1 M
25 mg/kg
cytochrome c, caspase-3, caspase-9, Bcl-2 Synergized the antitumor effects of vemurafenib through suppressing cell proliferation and cancer-stem cell traits by targeting NF-κB/iNOS/hTERT signaling In vitro, in vitro G361, A431, A375, SK-Mel-28 [142]
Breast cancer 1 mM caspase-3 Increased apoptosiss and decreased proliferation in cancer cells In vitro MDA-MB-231, MCF-7 [143]
Pancreatic cancer 10–10, 10–12 M Bax, Bcl-2, caspase-3, caspase-9 Improved the anti-tumor effects of gemcitabine through apoptosis regulation In vitro PANC-1 [144]
Breast cancer 25 µM Bax, Bcl-2 Decreased the cell proliferation and increased apoptosis and differentiation in cancer cells In vitro MCF-7, HEK293 [145]
Leukemia 1 mM Bcl-2, Bcl-xL Synergistic effect on chemotherapeutic agent In vitro HL-60 [146]
Breast cancer 0.1–5 mm
1 mg/kg
- Melatonin caused apoptosis induction, angiogenesis inhibition, and activation of T helper 1 In vitro, in vivo EMT6/P [147]
Colorectal cancer 1 mM BAX, caspase3, PARP1 Induced mitochondria-induced cellular apoptosis In vitro SNUC5/WT [71]
Breast cancer 1 nM and 100 nM c-IAP1, XIAP, survivin, MCL-1, BCL-2, Enhanced cytotoxic effects of arsenic trioxide and apoptosis induction In vitro MCF-7 [148]
Pancreatic cancer 0.1, 1, or 2 mM
40 mg/kg
cytochrome c
XIAP, Mcl-1, Survivin, Bcl-2, PARP
Reinforced the anticancer effect of sorafenib via downregulation of PDGFR-β/STAT3 signaling In vitro, in vivo MIAPaCa-2, PANC-1 [149]
Glioblastoma 1 mM, 3 mM - Delayed cell cycle progression and potentiated the decrease of cell survival due to treatment with temozolomide In vitro U87MG [150]
Oral cancer 1 mM
40 mg/kg
cyclin D1, PCNA, Bcl-2, Bax Suppressed the invasion and migration of cancer cells through repressing ROS-activated Akt signaling
Hampered vasculogenic mimicry and retarded tumorigenesis of cancer cells
In vitro, in vivo SCC25, SCC9, Tca8113, Cal27, and FaDu [48]
Gastric cancer 10−4 mol/L Bcl-2, Bax, p53, caspase3, Hyperbaric oxygen sensitized cancer cells to melatonin-mediated apoptosis In vitro SGC7901 [151]
Thyroid cancer 1, 2, 4, 8, 15 mM
25 mg/kg
caspase 3/7, PARP, cytochrome c Reduced cell viability, inhibited cell migration and induced apoptosis
Synergized with irradiation to induce cytotoxicity to thyroid cancer cells
In vitro, in vivo 8505c, ARO [152]
Gastric cancer 1, 2, 3, 4 or 5 mM Bax, Bcl-xL, caspase-9, caspase-3 Induced cell cycle arrest and induced apoptosis In vitro SGC-7901 [153]
Neural cancer 0.5, 1 mM Bax, Bcl-2, caspase-9, cytochrome c Mitochondrial cytochrome P450 1B1 is responsible for melatonin-induced apoptosis In vitro U118, SH-SY5Y, U87, U251, A172 [154]
Gastric cancer 1, 5 µM - Inhibited the proliferation of cancer cells by regulating the miR-16-5p-Smad3 pathway In vitro BSG823, SGC-7901 [155]
Head and neck squamous cell carcinoma 0.1, 0.5, or 1 mM Bax, Bcl-2 Enhanced ROS production, increased apoptosis and mitophagy, and could be used as an adjuvant agent with rapamycin In vitro Cal-27, SCC-9 [94]
Ovarian cancer, colorectal cancer 0.1, 1.0, and 10 μM - Induced apoptosis and showed antioxidant effects In vitro DLD1, A2780 [156]
Cervical cancer 1 mM JNK/Parkin/mitophagy, caspase-9 Sensitized cancer cells to cisplatin-mediated apoptosis by suppression of JNK/Parkin/mitophagy pathways In vitro HeLa [100]
Melanoma
Breast cancer
Melatonin: 10−5 − 10−3 M
Melatonin analogues (UCM 1037):
10−6 − 10−4 M and 16 mg/Kg
Bcl-2, Bax, caspase-3 Inactivated mitophagy by suppression of JNK/Parkin, leading to the inhibition of anti-apoptotic mitophagy
Sensitized cervical cancer cells to cisplatin-mediated apoptosis
In vitro, in vivo DX3, WM-115, MCF-7, MDA-MB231 [157]
Bladder cancer 10 mg/kg
1.0 mM
caspase-3, Bcl-2, BAX Synergized the inhibitory effects of curcumin against the growth of bladder cancer through increasing the anti-proliferation, anti-migration, and pro-apoptotic properties In vivo, in vitro T24, UMUC3, 5637 [158]
Colorectal cancer 1 mM caspase-3 Increased the sensitivity of cancer cells to 5-FU In vitro HT-29 [159]
Lung cancer 25 mg/kg
1 mM
caspse-9, Bcl-2, PARP, cytochrome C Increased antitumor activities of berberine through activating caspase/Cyto C and suppressing AP-2β/hTERT, NF-κB/COX-2 and Akt/ERK pathways In vitro, in vivo H1299, A549 [160]
Gastric cancer 1, 2 mM caspase-3, Bcl-2, BAX Suppressed cell viability, clone formation, cell migration and invasion and induced apoptosis In vitro AGS [161]
Ovarian cancer 200 μg/100 g b.w p53, BAX, caspase-3, Bcl-2, survivin Promoted apoptosis In vivo - [162]
Cervical cancer 1 mM Caspase-3 Enhanced cisplatin-mediated cytotoxicity and apoptosis In vitro HeLa [163]
Rhabdomyosarcoma 0.01, 0.1, 1, 2 mM Bax, Bcl-2, caspase-3 Enhanced the sensitivity of cancer cells to apoptosis In vitro U57810, U23674 [164]
Hepatocellular carcinoma 2 mM PARP, Bax Ceramide metabolism regulated apoptotic and autophagy cell death mediated by melatonin In vitro HepG2 [96]
Neuroblastoma 0.25, 0.5, 1, 2 mM - Exerted cytotoxic potentials against cancer cells In vitro SH-SY5Y [165]
Colorectal cancer 0.1–2.0 mM HDAC4, Bcl-2, CaMKIIα Melatonin-induced apoptosis depends on the nuclear import of HDAC4 and subsequent H3 deacetylation by CaMKIIα inactivation In vitro LoVo [117]
RCC, CRC, Head and neck cancer, Prostate cancer, breast cancer 1 mM PUMA, Mcl-1, Bcl-xL, Bim, COX-2 Enhanced antitumor effects by COX-2 downregulation and Bim up-regulation In vitro MDA-MB-231, Caki, HN4,
HCT116, PC3
[123]
Cholangiocarcinoma 1 nM, 1 μM
0.5, 1, 2 mM
Caspase-3/7, cytochrome c Functioned as a pro-oxidant through activating ROS-dependent DNA damage and hence leading to the apoptosis of cancer cells In vitro KKU-M055, KKU-M214 [166]
Lung cancer 1–5 mM caspases-3/7 Increased cisplatin-induced cytotoxicity and apoptosis in lung cancer cells In vitro SK-LU-1 [167]
Gastric cancer 25, 50, 100 mg/kg Bcl-2, Bax, p21, p53 Inhibited tumor growth by apoptosis induction In vivo MFC [168]
Lung cancer 1, 5, 10 mM caspase-3/7 Showed anticancer impacts by changing biomolecular structure of lipids, nucleic acids and proteins In vitro SK-LU-1 [169]
Lung cancer 10−13 M (subphysiological), 10−10 M
(physiological)
10−7, 10−4, 10− 3 M
(Cytotoxic)
CCAR2 Cell cycle and apoptosis regulator 2 (CCAR2) is critical for maintaining cell survival in the presence of melatonin In vitro A549, A427 [170]
Lung cancer 500 μM Bcl-2, Bcl-xL, TRAIL Induced apoptosis in TRAIL-resistant hypoxic tumor cells trough diminishing the anti-apoptotic signals induced by hypoxia In vitro A549 [114]
Breast cancer 1 nM p53, MDM2/MDMX/p300 Enhanced p53 acetylation by regulating the MDM2/MDMX/p300 pathway In vitro MCF-7 [113]
Colorectal cancer 10 μM Bax, Bcl-xL, Activated cell death programs early and induced G1-phase arrest at the advanced phase In vitro HCT116 [171]
Renal cancer 0.1, 0.5,1 mM Bim Induced apoptosis by the upregulation of Bim expression In vitro Caki [172]
Leukemia 1 mM Bax, cytochrome c Induced apoptosis by a caspase-dependent but ROS-independent manner In vitro Molt-3 [173]
Gastric cancer 10–4 mol/l Caspase-3 Inhibited tumor cell proliferation and reduced the metastatic potential of cancer cells In vitro SGC7901 [174]
Colorectal cancer 1 mM caspase-3/9, PARP Potentiated the anti-proliferative and pro-apoptotic impacts of Ursolic acid in cancer cells In vitro SW480, LoVo [175]
Pancreatic cancer 1.5 mmol/L
20 mg/kg
Bax, Bcl-2 Melatonin may be a pro-apoptotic and pro-necrotic molecule for cancer cells by its regulation of Bcl-2/Bax balance In vitro, in vivo SW-1990 [176]
Breast cancer 10–3 M COX-2/PGE2, p300/NF-κB, PI3K/Akt, Apaf-1/caspase-3/9 Inhibited cell proliferation and induced apoptosis In vitro MDA-MB-361 [32]
Hepatocellular carcinoma 10–9, 10–7, 10–5, 10–3 μM CHOP, Bcl-2, Bax, COX-2 Sensitized cancer cells to ER stress-mediated apoptosis by downregulating COX-2 expression, enhancing the levels of CHOP and reducing the Bcl-2/Bax ratio In vitro HepG2 [73]
Ovarian cancer 0, 0.5, 1, 2 mM ERK/p90RSK/HSP27 Enhanced cisplatin-mediated apoptosis through the inactivation of ERK/p90RSK/HSP27 pathway In vitro SK-OV-3 [122]
Gastric cancer 2 mM NF-κB, MAPK Conflicting growth signals in cells may suppress melatonin efficacy in the treatment of gastric cancer In vitro SGC7901 [177]
Hepatocellular carcinoma 10–3, 10–5, 10–7, 10–9 mmol/L COX-2, Bcl-2, Bax Melatonin was shown as a novel selective ATF-6 inhibitor that can sensitize human hepatoma cells to ER stress inducing apoptosis In vitro HepG2 [74]
Glioma 1 μM - Inhibited miR-155 expression and hence repressed glioma cell proliferation, invasion and migration In vitro U87, U373, U251 [178]
Breast cancer 1 mM caspase-3, hTRA, XIAP, TNFRII, P53, P21, Livin, IGF-1R, IGF-1, IGFPB-6, IGFBP-5, IGFBP-3, DR6, CYTO-C Showed pro-apoptotic, anti-angiogenic and oncostatic properties In vitro MDA-MB-231, MCF-7 [179]
Leukemia 1 mM ROS, caspase-3/8/9 Enhanced apoptotic effects of hydrogen peroxide In vitro HL-60 [180]
Renal cancer 1 nM CHOP, PUMA PUMA up-regulation contributed to the sensitizing impact of melatonin plus kahweol on apoptosis In vitro Caki [181]
Pancreatic cancer 10−8 –10−12 M Bcl-2, Bax, caspase-9 Induced pro-apoptotic pathways by interaction with the Mel-1 A/B receptors In vitro PANC-1 [182]
Ewing sarcoma 50 μM-1 mM caspase-3/8/9, Bid Showed cytoprotective effects on noncancer cells and induced apoptosis In vitro SK-N-MC [183]
Glioma 1 mM Survivin, Bcl-2 Increased cell sensitivity to TRAIL-mediated cell apoptosis In vitro A172, U87 [184]
Leukemia 1 mM
250 mg/kg
Bax, Bcl-2, p53 Enhanced radiation-mediated apoptosis in cancer cells, while decreasin radiation-meditated apoptosis in normal cells In vitro, in vivo Jurkat [185]
Breast cancer 1 nM Caspase-7/9, p53, MDM2, PARP, Bcl-2, Bax Induced apoptosis in cancer cells In vitro MCF-7 [116]
Hepatocellular carcinoma 1000–10,000 μM caspase-3/8/9, PARP, cytochrome c, Bax, p53, p21 Induced cell cycle arrest and apoptosis In vitro HepG2 [115]
Pheochromocytoma 100 μM GSH Apoptotic and antioxidant effects In vitro PC12 [186]
Neuroblastoma 100 μM Caspase-3 Induced apoptosis In vitro SK-N-MC [187]
Leukemia
Cervical cancer
50 μM Caspase-3 Protectted normal and cancer cells against genotoxic treatment and apoptosis induced by idarubicin In vitro K562,
HeLa
[188]
Colorectal cancer 1 mM Caspase-3 Potentiated flavone-mediated apoptosis in cancer cells In vitro HT-29 [189]
Breast cancer 1 nM Bax, p53, p21, WAF1, bcl-XL, bcl-2 Decreased cancer cell proliferation through regulating cell-cycle length by the control of the p53-p21 pathway In vitro MCF-7 [190]
Esophageal cancer 0–5 mM
25 mg/kg
PARP, caspase-3/7/8 Increased cytotoxicity of 5-Fu In vivo, in vitro KYSE30, KYSE150, KYSE410, KYSE520 [191]
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