Abstract
Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) 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 SQ1 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 SQ2 showed improved solubility and reached a 30–40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of SQ1 and SQ2 in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAFV600E and NRASQ61R, respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to SQ1 or SQ2. Overall, these studies showed that SQ1 and SQ2 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 SQ1 and SQ2, 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.
Highlights
Seriniquinone (SQ1, Figure 1A), a natural product isolated from a marine bacterium of the genus Serinicoccus, displays potent cytotoxic activity against a panel of tumor cell lines with particular selectivity towards melanoma [1]
The IC50 value for SQ1 in melanoma cells ranged from 0.06 μM in SK-MEL-19 to 1.4 μM for
The most prominent effects were obtained for melanoma cell lines (SK-MEL-19, SK-MEL-28, and SK-MEL-147)
Summary
Seriniquinone (SQ1, Figure 1A), a natural product isolated from a marine bacterium of the genus Serinicoccus, displays potent cytotoxic activity against a panel of tumor cell lines with particular selectivity towards melanoma [1]. This activity is associated with the induction of autophagy and apoptosis [1]. We report on the activity of these materials in cell lines representing key mutation profiles observed in melanoma using SK-MEL-28 and SK-MEL-147 cell lines. Molecules 2021, 26, 7362 representing key mutation profiles observed in melanoma using SK-MEL-28 and SKMEL-147 cell lines We report on the activity of these materials in cell lines representing key mutation profiles observed in melanoma using SK-MEL-28 and SK-MEL-147 cell lines. 4.0/).
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