Anti-melanoma effects of concomitant inhibition of SIRT1 and SIRT3 in Braf V600E/Pten NULL mice

Novel therapeutic strategies are required for the effective and lasting treatment of metastatic melanoma, one of the deadliest skin malignancies. In this study, we determined the anti-melanoma efficacy of 4'-bromo-resveratrol (4'-BR), which is a small molecule dual inhibitor of SIRT1 and SIRT3 in a BrafV600E/PtenNULL mouse model that recapitulates human disease, including metastases. Tumors were induced by topical application of 4-hydroxy-tamoxifen on shaved backs of 10-week-old mice, and the effects of 4'-BR (5-30 mg/kg b.wt.; intraperitoneally; 3d/week for 5 weeks) were assessed on melanoma development and progression. We found that 4'-BR at a dose of 30 mg/kg significantly reduced size and volume of primary melanoma tumors, as well as lung metastasis, with no adverse effects. Further, mechanistic studies on tumors showed significant modulation in markers of proliferation, survival and melanoma progression. As SIRT1 and SIRT3 are linked to immunomodulation, we performed differential gene expression analysis via NanoString PanCancer Immune Profiling panel (770 genes). Our data demonstrated that 4'-BR significantly downregulated genes related to metastasis-promotion, chemokine/cytokine-regulation, and innate/adaptive immune functions. Overall, inhibition of SIRT1 and SIRT3 by 4'-BR is a promising anti-melanoma therapy with anti-metastatic and immunomodulatory activities warranting further detailed studies, including clinical investigations.