Quercetin Modulates the p53 Signaling Pathway to Induce Apoptosis: Combating Vemurafenib Resistance in Melanoma

Background: Melanoma is an aggressive skin cancer with a high potential for developing resistance to targeted therapies. One such therapy, vemurafenib, specifically inhibits the B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation, a key driver of melanoma progression. However, acquired resistance to vemurafenib remains a major challenge, necessitating alternative treatment strategies. Quercetin, a natural flavonoid with well-documented anticancer properties, has demonstrated potential in overcoming drug resistance, making it a promising candidate for melanoma therapy.

Materials and Methods: This study evaluated the effects of quercetin on both melanoma A375.S2 and vemurafenib-resistant A375.S2/VR cells. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while apoptosis was measured through caspase-3/-7 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Ribonucleic acid (RNA) sequencing and Ingenuity Pathway Analysis (IPA) were employed to identify the mechanisms underlying quercetin’s effects.

Results: Quercetin significantly reduced cell viability in a dose-dependent manner in both cell lines, with A375.S2/VR cells requiring higher concentrations, while HaCaT cells, a normal keratinocyte cell line, remained unaffected, accompanied by an increase in apoptotic cell numbers and caspase-3/-7 activity. RNA sequencing revealed 379 differentially expressed genes, with IPA indicating significant involvement of the p53 signaling pathway. Increased caspase-3/-7 activity and apoptotic cell numbers confirmed apoptosis induction. Key regulators and pathways involved in apoptosis and inflammation were identified.

Conclusions: Quercetin effectively induces apoptosis in vemurafenib-resistant melanoma cells by modulating the p53 signaling pathway, presenting a promising therapeutic strategy for overcoming drug resistance. Furthermore, in vivo studies are needed to validate these findings and explore clinical applications.