Calcitriol, the active form of vitamin D, induces cell death and purinergic signaling modulation in cutaneous melanoma cells

Abstract Cutaneous melanoma (CM) is the most aggressive form of skin cancer, characterized by high metastatic potential and resistance to conventional therapies. Evidence suggests that modulation of purinergic signaling, interleukin-6 (IL-6), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) may represent promising strategies for treating CM. Calcitriol, the active form of vitamin D, has demonstrated antineoplastic potential across different cancer types. In addition, reports have shown that purinergic signaling can be modulated by calcitriol. However, its mechanism of action on the purinergic system in melanoma remains poorly explored. In this study, we investigated the antineoplastic effects of calcitriol on human cutaneous malignant melanoma cell lines, with a focus on the purinergic system. The cells A375 and SK-MEL-28 were treated with calcitriol at 1, 10, and 50 nM for 24 h, and we analyzed cell viability, mitochondrial membrane potential, apoptotic body detection, migration, and ectonucleotidase enzymatic activity. We also analyzed the expression of ectonucleotidases (CD39 and CD73) and IL-6/NLRP3. We found that calcitriol significantly reduced A375 cell viability, altered mitochondrial potential, inhibited cell migration, and induced the formation of apoptotic bodies. These effects were not observed in SK-MEL-28. Moreover, calcitriol modulated the ectonucleotidases activity and downregulated CD39 and CD73 expression. Additionally, the treatments downregulated IL-6 and NLRP3 expression. Thus, our findings demonstrate that calcitriol exerts antineoplastic effects on melanoma cells via mitochondrial dysfunction, apoptosis-related alterations, inhibition of migration, and modulation of purinergic and inflammatory mediators. Therefore, calcitriol is a promising adjuvant for CM therapy.