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

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]