Melatonin inhibits growth of B16 melanoma in C57BL/6 mice

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) has oncostatic properties in a wide variety of tumors. In melanoma, melatonin displayed growth suppressive effects in cultured cell lines and tumors. Thus far, however, there is no evidence of orally administrated melatonin reducing melanoma tumor growth. Therefore, the current study investigated the preventive effect of melatonin on C57BL/6 mice injected with B16-F10 murine metastatic melanoma cells. The animals were divided into two groups; control (vehicle) and melatonin pre-treated with oral melatonin in the drinking water (10 mg/kg/day) for 15 days. Grossly, the control animals had a significant exponential increase in tumor size until day 33, and all control animals were dead by day 38; conversely, melatonin pre-treated mice demonstrated delayed tumour appearance as well as decreased tumour volume and increased survival rates. PCNA immunostaining corroborated these data and demonstrated a significant reduction in the number of proliferating cells in the melatonin-treated mice (P < 0.005). Interestingly, histopathological analysis revealed the presence of undifferentiated and pleomorphic cells associated with higher mitotic rate in the control group, while epithelioid-shaped cells, sometimes containing melanin were clearly identified in melatonin-treated animals. Mitochondrial parameters measurement showed greater PTP opening and increased mitochondrial nitrite level associated in melatonin-pretreated animals. Finally, the decreased P-ERK1,2 cytoplasmic expression in melatonin mice compared with the controls supports the conclusion that the MAPK signalling pathway is repressed by melatonin in B16-F10 melanoma. Collectively, these results suggest for the first time that orally-administered melatonin reduces malignant melanoma progression in vivo and increases the percent of survival by lowering tumor cells proliferation due to mitochondrial dependent cytotoxicity and decreased P-ERK1,2 expression. This study demonstrates the chemopreventive potential of melatonin against malignant melanoma in C57BL/6 mice.

Melatonin as a Repurposed Drug for Melanoma Treatment

“…To that end, C57BL/6 mice were pre-treated orally with or without melatonin for 14 days followed by subcutaneous implantation of melanoma cells and then the treatment continued at the end of the study. The data demonstrated that melatonin treatment significantly reduced tumor size and increased the survival probability of mice, which was correlated with tumor size as compared to the vehicle-treated control mice [ 47 ]. Mechanistically, melatonin-induced decreased tumor growth was mediated via increased tumor cell degeneration and necrosis as well as reduced tumor angiogenesis, mitotic index, cell proliferation, and activation of the ERK1/2 signaling pathway.…”

“…Importantly, while no differences in the mitochondrial complex activities were noted, a significantly increased level of mitochondrial nitrites was found in melatonin-treated mice compared with the control mice. Overall, the findings indicated the potential chemopreventive efficacy of melatonin in the experimental melanoma model [ 47 ].…”