Seriniquinones as Therapeutic Leads for Treatment of BRAF and NRAS Mutant Melanomas

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-12, Vol.26 (23), p.7362
• Main Authors: Hirata, Amanda S, Rezende-Teixeira, Paula, Machado-Neto, João Agostinho, Jimenez, Paula C, Clair, James J La, Fenical, William, Costa-Lotufo, Leticia V
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agent; Apoptosis; Apoptosis - drug effects; Aqueous solutions; Autophagy; Autophagy - drug effects; Cancer; Cell growth; Cell Line, Tumor; Cell lines; Cytotoxicity; dermcidin; Drug Discovery; Gene expression; Genes; GTP Phosphohydrolases - genetics; Humans; marine pharmacology; Materials selection; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Membrane Proteins - genetics; Mutants; Mutation; Mutation - genetics; natural products; Peptides; Phagocytosis; Proteins; Proto-Oncogene Proteins B-raf - genetics; Quinones - chemistry; Quinones - pharmacology; Selectivity; Serine - analogs & derivatives; Serine - pharmacology; Solubility; Tumors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26237362

Isolated from the marine bacteria sp., seriniquinone ( ) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility of in both organic and aqueous media has complicated its preclinical evaluation. In response, our team turned its effort to explore analogues with the goal of returning synthetically accessible materials with comparable selectivity and activity. The analogue showed improved solubility and reached a 30-40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of and in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAF and NRAS , respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to or . Overall, these studies showed that and demonstrated comparable activity and modulation of dermcidin expression. These studies are further supported through the evaluation of a panel of basal expression of key-genes related to autophagy and apoptosis, providing further insight into the role of these mutations. To explore this rather as a survival or death mechanism, autophagy inhibition sensibilized BRAF mutants to and , whereas the opposite happened to NRAS mutants. These data suggest that the seriniquinones remain active, independently of the melanoma mutation, and suggest the future combination of their application with inhibitors of autophagy to treat BRAF-mutated tumors.