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 antimelanoma 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 mice aged 10 weeks, and the effects of 4'-BR (5‒30 mg/kg of
body weight, intraperitoneally, 3 days per 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 the size and volume of primary
melanoma tumors as well as lung
metastasis with no adverse effects. Furthermore, mechanistic studies on
tumors showed significant modulation in the markers of proliferation, survival, and
melanoma progression. Because
SIRT1 and
SIRT3 are linked to
immunomodulation, we performed differential gene expression analysis using a PanCancer Immune Profiling Panel (770 genes). Our data showed that 4'-BR significantly downregulated the 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 antimelanoma
therapy with antimetastatic and immunomodulatory activities warranting further detailed studies, including clinical investigations.