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.