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

Abstract

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

Melanogenesis Is Directly Affected by Metabolites of Melatonin in Human Melanoma Cells

“…Furthermore, regulation of their endogenous production/metabolism can serve as a rational strategy for targeted therapies of melanoma patients. Thus, based on results presented here and hypothesized recently Kleszczy ński and Böhm [91] and others [92,93], we are tempted to claim that melatonin, and also its metabolites, may boost commonly used BRAF/MEK inhibitors; however, these investigations still need to be carefully checked using in vitro and in vivo models.…”

Melatonin as a Repurposed Drug for Melanoma Treatment

“…Notably, a few clinical trials reported increased doses of pharmacotherapy to patients, which was associated with adverse effects such as skin rash, keratoacanthoma, hyperkeratosis, headache, arthralgia, pyrexia, and atopic dermatitis, and 7% to 9% cases were shown to develop cardiac abnormalities that include decreased ejection fraction and interstitial lung diseases such as pneumonitis [ 28 ]. Therefore, due to these ongoing challenges associated with conventional therapies, including adverse side effects, various adjuvant therapies, including melatonin are being explored as repurposed drugs in cellular and preclinical models because of their anticancer properties in melanoma [ 29 ].…”

Melatonin: A Potential Regulator of DNA Methylation

“…Melatonin reduces the rates of cancer initiation, progression, metastasis and migration [ 36 , 37 , 38 , 39 ], angiogenesis, and inflammation [ 40 , 41 , 42 ]. On the other hand, melatonin can regulate the immune system [ 43 , 44 ] and oxidative stress [ 19 , 30 , 38 , 45 , 46 , 47 , 48 ], thereby repressing many malignancies [ 49 ].…”