The World Health Organization reported that approximately 324,000 new cases of
melanoma skin cancer were diagnosed worldwide in 2020. The incidence of
melanoma has been increasing over the past decades. Targeting apoptotic pathways is a potential therapeutic strategy in the transition to preclinical models and clinical trials. Some naturally occurring products and synthetic derivatives are apoptosis inducers and may represent a realistic option in the fight against the disease. Thus,
chalcones have received considerable attention due to their potential cytotoxicity against
cancer cells. We have previously reported a
chalcone containing an
indole and a
pyridine heterocyclic rings and an α-bromoacryloylamido radical which displays potent antiproliferative activity against several tumor cell lines. In this study, we report that this
chalcone is a potent apoptotic inducer for human
melanoma cell lines SK-MEL-1 and MEL-HO. Cell death was associated with mitochondrial
cytochrome c release and
poly(ADP-ribose) polymerase cleavage and was prevented by a non-specific
caspase inhibitor. Using SK-MEL-1 as a model, we found that the mechanism of cell death involves (i) the generation of
reactive oxygen species, (ii) activation of the extrinsic and intrinsic apoptotic and
mitogen-activated protein kinase pathways, (iii) upregulation of TRAIL, DR4 and DR5, (iv) downregulation of p21Cip1/WAF1 and, inhibition of the NF-κB pathway.