Melanoma prevention strategy based on using tetrapeptide α‐MSH analogs that protect human melanocytes from UV‐induced DNA damage and cytotoxicity

Abstract

Melanoma is the deadliest form of skin cancer, with no cure for advanced disease. We propose a strategy for melanoma prevention based on using analogs of alpha-melanocyte stimulating hormone (alpha-MSH) that function as melanocortin 1 receptor (MC1R) agonists. Treatment of human melanocytes with alpha-MSH results in stimulation of eumelanin synthesis, reduction of apoptosis that is attributable to reduced hydrogen peroxide generation and enhanced repair of DNA photoproducts. These effects should contribute to genomic stability of human melanocytes, thus preventing their malignant transformation to melanoma. Based on these findings, we synthesized and tested the effects of 3 tetrapeptide alpha-MSH analogs, Ac-His-D-Phe-Arg-Trp-NH2, n-Pentadecanoyl- and 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2, on cultured human melanocytes. The latter two analogs were more potent than the former, or alpha-MSH, in stimulating the activity of tyrosinase, thus melanogenesis, reducing apoptosis and release of hydrogen peroxide and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation (UVR). The above analogs are MC1R agonists, as their effects were abrogated by an analog of agouti signaling protein, the physiological MC1R antagonist, and were absent in melanocytes expressing loss-of-function MC1R. Analogs, such as 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2 with prolonged and reversible effects, can potentially be developed into topical agents to prevent skin photocarcinogenesis, particularly melanoma.

RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

“…Though MC1R dysfunction is clearly linked with defective tanning (D’Orazio et al, 2006) and altered AKT regulation (Cao et al, 2013), MC1R signaling also protects melanocytes against carcinogenesis independent of pigmentation (Hauser et al, 2006). Mediated by robust cAMP second messenger generation, MC1R signaling enhances the rate of clearance of UV-induced DNA photodamage (Abdel-Malek et al, 2006; Dong et al, 2010; Kadekaro et al, 2012). Herein, we report that MC1R signaling enhances NER by a novel and direct PKA-mediated phosphorylation of ATR on Ser435.…”

Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention

“…Our data showed our tetra-and tripeptide analogs had no effect on cultured human melanocytes that express loss-of-function MC1R due to expression of 2 RHC alleles [4,6]. However, this does not negate the significance of utilizing selective MC1R analogs for skin cancer, including melanoma prevention, given the millions of individuals that stand to benefit from this strategy, particularly those expressing mutations in other skin cancer or melanoma susceptibility genes, and those heterozygous for MC1R RHC variants.…”

“…This peptide proved to be 1000 fold more potent than a-MSH in activating the MC1R, as measured by increasing cAMP levels. It also proved to be more potent than a-MSH in stimulating the activity of tyrosinase, hence melanogenesis, enhancing repair of UV-induced photoproducts, and reducing UV-induced apoptosis of human melanocytes ( [4]. Moreover, this tetrapeptide had a more prolonged residual effect than a-MSH on stimulation of tyrosinase activity [4].…”

“…For that, we attempted to design a-MSH analogs that are hydrophilic, in order to facilitate their penetration through the stratum corneum and the epidermal layers of human skin. We have designed n-capped tetrapeptide a-MSH analogs, based on the lead compound 4-phenylbutyryl-His-D-Phe-Arg-Trp-NH 2 [4]. This peptide proved to be 1000 fold more potent than a-MSH in activating the MC1R, as measured by increasing cAMP levels.…”

Prevalence and Post-exposure Prophylaxis use for Needlestick Injuries among Health Care Providers in a Tertiary Care Hospital in Kochi, India

“…The main reasons for underreporting might be due to the fact that a significant proportion of HPs did not know about the existence of a PEP service and were unaware about whom to contact in the event of an occupational exposure. Other reasons include an underestimation of HIV transmission and an unwillingness to take anti-retroviral drugs, as has been noted in previous studies (7)(8)(9)(10)(11)(12).…”