Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT‐1 melanoma cells

Kleszczyński, Konrad; Kim, Tae Kang; Bilska, Bernadetta; Sarna, Michał; Mokrzyński, Krystian; Stegemann, Agatha; Pyza, Elżbieta; Reíter, Russel J.; Steinbrink, Kerstin; Böhm, Markus; Słomiński, Andrzej

doi:10.1111/jpi.12610

Cited by 38 publications

(44 citation statements)

References 91 publications

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“…[ 25 ] As outlined above, melatonin significantly suppresses the cAMP‐protein kinase A (PKA) axis that controls microphthalmia‐associated transcription factor (MITF)‐induced melanin synthesis. [ 26,35,36 ] This is in accordance with previous data showed by Tao and Zhu (2018) [ 37 ] who showed that the transcription factor CREB (cAMP response element‐binding) protein is regulated by melatonin. Of note, melanocyte growth factors that turn on proliferation synergistically not only enhance MAPK signalling but also phosphorylation of CREB.…”

Section: Premisessupporting

confidence: 91%

Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?

Kleszczyński

Böhm

2020

Experimental Dermatology

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Melanoma is one of the deadliest cancers in the Western world with an increasing incidence. [1,2] Our most recently approved therapies against metastatic melanoma, especially checkpoint inhibitors and targeted therapy with BRAF/MEK inhibitors, have largely replaced chemotherapy. The 5-year survival rate of patients with stage IV melanoma has increased to 15%-20%. [3-5] Nevertheless, the overall survival rate and drug resistance remain a challenge for targeted therapy. According to clinical trials, BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most effective regimens for the treatment of advanced BRAF V600E-mutated melanoma. The median progression-free survival of combinational therapies are 9.4 months (dabrafenib/trametinib), 11 months (vemurafenib/cobimetinib) or 14.9 months (encorafenib/binimetinib) compared to monotherapies, that is 6 months (vemurafenib), 5.8 months (dabrafenib) and 9.6 months (encorafenib). [6-10] However, these therapies are associated with adverse effects, for example elevated liver enzymes, fatigue, nausea, and photosensitivity (vemurafenib/cobimetinib), pyrexia, fatigue, rash and hypertension (dabrafenib/trametinib), enhancement of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and retinopathy (encorafenib/binimetinib). [8,9] Therefore, searches for novel approaches or complementary/combinational treatments and those with reduced side effects are ongoing. For examples, combination of targeted therapy with checkpoint blockers [11] or with talimogene laherparepvec vaccination is explored. [12,13] 2 | PREMIS E S Melatonin (N-acetyl-5-methoxytryptamine) is an indole produced mainly by the pineal gland. It is a well-known endogenous

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Section: Premisessupporting

confidence: 91%

Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?

Kleszczyński

Böhm

2020

Experimental Dermatology

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“…In human melanocytes, melatonin appears not to have a major influence on the pigmentation [38]. However, in human melanoma cells melatonin may both stimulate tyrosinase activity and pigmentation, as described in SK-MEL-28 and SK-MEL-1 cells [6,39], or decrease melanogenesis as reported in MNT-1 melanoma cells [3]. The basis of differential response of melanoma cells to melatonin treatment is unknown and it could be multifactorial.…”

Section: Discussionmentioning

confidence: 98%

“…In mammals, the pineal gland secretes melatonin into the blood and cerebrospinal fluid to exert a variety of well-documented physiological functions [2]. Among the vast array of biological functions exhibited by melatonin, its antineoplastic properties have attracted significant attention involving cell death, oncostatic properties, and differentiation [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

Perdomo

Quintana

González

et al. 2020

IJMS

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Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3β seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3β. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.

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“…Several studies reported on the anti-tumor actions of melatonin against malignant melanoma both in vitro or in vivo (6,16,(23)(24)(25)(26)(27)(28). Thus, the present study was undertaken to assess the ability of orally-administered melatonin, an otherwise non-toxic chemoprotective agent against malignant B16-F10 melanoma cells subcutaneously injected into C57BL/6 mice.…”

Section: Introductionmentioning

confidence: 99%

Melatonin inhibits growth of B16 melanoma in C57BL/6 mice

et al. 2020

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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.

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Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT‐1 melanoma cells

Cited by 38 publications

References 91 publications

Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?

Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?

Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

Melatonin inhibits growth of B16 melanoma in C57BL/6 mice

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