Table 2.

Melatonin treatment reduces cancer-associated osteolytic factors.

Type of Cancer	Osteolytic Factors	Dosage	Model	Outcomes	Ref.
Pancreatic, cervical, lung	VEGF HIF-1α	Cells: 1 nM or 1 mM	Cell lines: PANC-1, HeLa and A549	At the high concentration (1 mM), melatonin inhibited VEGF mRNA and protein levels, as well as HIF-1α protein, in all three human cancer cell lines.	[83]
Prostate	HIF-1α	Cells: 1 mM	Cell lines: DU145, PC-3, and LNCaP	Melatonin-induced inhibition of HIF-1α protein expression, HIF-1α transcriptional activity and the release of VEGF in all three cell lines correlated with dephosphorylation of p70S6K and its direct target RPS6.	[84]
Bladder	COX-2	Cells: 1 mM	Cell lines: T24, UMUC3 and 5637	When combined with curcumin, melatonin enhanced the inhibitory effects of curcumin on COX-2 activity and enhanced the antiproliferative, antimigratory and proapoptotic activities of curcumin in bladder cancer cells.	[85]
		Animal: 10 mg/kg	Animal: BALB/c nude mice
Osteosarcoma	SOX9	Cells: 0.5 mM	Cell lines: HOS and U2-OS	Melatonin suppressed osteosarcoma cell migration and invasion and also significantly inhibited osteosarcoma metastasis in a mouse model of osteosarcoma. These effects were achieved by downregulating SOX9-mediated signaling.	[86]
		Animal: 100 mg/kg	Animal: BALB/c nude mice
Gastric adenocarcinoma	MMP-2 MMP-9	Cells: 0.1, 0.5 or 1.5 mM	Cell lines: MGC80-3 and SGC-7901	Melatonin suppressed IL-1β-induced EMT in human gastric adenocarcinoma cells by targeting IL-1β/NF-κB/MMP-2/MMP-9 signaling.	[87]
Osteosarcoma	CCL24	Cells: 2 mM	Cell lines: HOS and U2OS	Melatonin inhibited the migratory potential and invasiveness of osteosarcoma HOS and U2OS cells. Melatonin also suppressed chemokine CCL24 levels in U2OS cells through the inhibition of the JNK pathway.	[81]
Oral	MMP-9	Cells: 100 and 250 μg/mL	Cell line: SAS	Areca nut extract components (betel quid chewing) may contribute to tumor invasion and metastasis by stimulating MMP-9 mRNA expression and secretion of oral cancer cells, which was inhibited by melatonin.	[88]
Osteosarcoma	MMP-9 HIF-1αTGF-β	Cells: 50, 100, 200, 500 and 1000 nM	Cell line: MG-63	Melatonin inhibits TGF-β1-induced EMT in osteosarcoma MG-63 cells by suppressing HIF-1α/Snail/MMP-9 signaling.	[49]
Prostate	MMP-13	Cells: 1 mM	Cell lines: DU145 and PC-3	Melatonin inhibited the migratory and invasive properties of prostate cancer cells, as well as MMP-13 expression, via the MT1 receptor and PLC, p38, and c-Jun signaling. Melatonin also inhibited prostate cancer metastasis and MMP-13 expression in an orthotopic prostate cancer model.	[89]
		Animal: 20 or 60 mg/kg	Animal: SCID mice
Breast	IL-6	Animal: 5 mg/kg	Animal: Female rats with DMBA-induced breast cancer	Combined zinc and melatonin therapy helped to prevent tumor growth by significantly disrupting the metabolism of several elements (iron, magnesium, zinc and copper), and by suppressing IL-6 levels and reducing tissue damage that encourages tumor growth.	[90]
Lung, prostate	RANKL	Cells: 0.1, 0.3 or 0.7 mM	Cell lines: A549 and PC-3	Melatonin inhibited RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which consequently prevented cancer-associated osteoclast differentiation. In animal models of lung and prostate bone metastasis, melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions.	[11]
		Animal: 20 or 60 mg/kg	Animal: BALB/c nude mice
Breast	Integrin β 1Elf-5	Cells: 5 mM	Cell lines: MCF-7 and MDA-MB-231	MEMP HT (5 mg melatonin, 0.5 mg estradiol, and 50 mg progesterone [half the recommended dose] hormone therapy) showed anticancer activity in ER+ and triple negative breast cancer cells. These effects were largely attributed to the melatonin component and MEMP HT working through MEK1/2- and MEK-5-dependent intracellular signaling cascades in each cancer cell line, modulating intracellular signaling proteins that encourage the inhibition of cellular proliferative and migratory activities.	[91]
Pancreatic stellate cells	COX-2 IL-6 TNF-α	Cells: 1000, 100, 10 or 1 μM	Cells: Primary PSCs from Wistar rat pups (3–5 days after birth)	Pharmacological concentrations of melatonin increased ROS production and reduced levels of glutathione in PSCs under hypoxic conditions. Melatonin downregulated NF-kB phosphorylation and COX-2, IL-6, and TNF-α expression.	[92]
Gastric	TGF-β1	Cells: 2 or 4 mM	Cell line: MFC	Melatonin inhibited gastric cancer cell proliferation in vitro by increasing TGF-β1 expression and also increased TGF-β1 levels in gastric cancer tumor tissues in vivo.	[93]
		Animal: 25, 50, or 100 mg/kg	Animal: H-2Kk mice

VEGF, vascular endothelial growth factor; HIF-1α, hypoxia-inducible factor 1-alpha; mRNA, messenger RNA; COX-2, cyclooxygenase-2; MMP, matrix metalloproteinase; IL-1β, interleukin 1 beta; EMT, epithelial-to-mesenchymal transition; NF-κB, nuclear factor kappa B; CCL24, C-C motif chemokine ligand 24; JNK, c-Jun N-terminal kinase; TGF-β1, transforming growth factor beta-1; MT₁ receptor, high-affinity G-protein-coupled melatonin receptor; PLC, phospholipase C; DMBA, 7,12-dimethylbenz(a)anthracene; RANKL, receptor activator of nuclear factor-kappa B ligand; MAPK, mitogen-activated protein kinase; ER⁺, estrogen receptor-positive; PSCs, pancreatic stellate cells; ROS, reactive oxygen species.