4'-Bromo-resveratrol, a dual Sirtuin-1 and Sirtuin-3 inhibitor, inhibits melanoma cell growth through mitochondrial metabolic reprogramming

Sirtuin-1 and -3 (SIRT1 and SIRT3) are important nicotinamide adenine dinucleotide (NAD⁺ )-dependent deacetylases known to regulate a variety of cellular functions. Studies have shown that SIRT1 and SIRT3 were overexpressed in human melanoma cells and tissues and their inhibition resulted in a significant antiproliferative response in human melanoma cells and antitumor response in a mouse xenograft model of melanoma. In this study, we determined the antiproliferative efficacy of a newly identified dual small molecule inhibitor of SIRT1 and SIRT3, 4'-bromo-resveratrol (4'-BR), in human melanoma cell lines (G361, SK-MEL-28, and SK-MEL-2). Our data demonstrate that 4'-BR treatment of melanoma cells resulted in (a) decrease in proliferation and clonogenic survival; (b) induction of Apoptosis accompanied by a decrease in procaspase-3, procaspase-8, and increase in the cleavage of Caspase-3 and poly (ADP-ribose) polymerase (PARP); (c) marked downregulation of proliferating cell nuclear antigen (PCNA); and (d) inhibition of melanoma cell migration. Further, 4'-BR caused a G0/G1 phase arrest of melanoma cells that was accompanied by an increase in WAF-1/P21 and decrease in Cyclin D1/Cyclin-dependent kinase 6 protein levels. Furthermore, we found that 4'-BR causes a decrease in lactate production, glucose uptake, and NAD⁺ /NADH ratio. These responses were accompanied by downregulation in Lactate Dehydrogenase A and glucose transporter 1 in melanoma cells. Collectively, our data suggest that dual inhibition of SIRT1 and SIRT3 using 4'-BR imparted antiproliferative effects in melanoma cells through a metabolic reprogramming and affecting the cell cycle and Apoptosis signaling. Therefore, concomitant pharmacological inhibition of SIRT1 and SIRT3 needs further investigation for melanoma management.