TheWorld 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 -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-B pathway.
