Identification of Experimental Prooxidants Targeting the Redox Vulnerability of Malignant Melanoma

Abstract

Cumulative evidence suggests that redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by pharmacological modulation of cellular oxidative stress. According to this emerging mechanism, pharmacological prooxidants may induce deviations from redox homeostasis causing cytotoxicity confined to malignant cells already at a high set point of constitutive oxidative stress leading to functional impairment, cell cycle arrest, and cell death. In contrast, the same prooxidant deviation from redox homeostasis is tolerated by nonmalignant cells that operate at a lower redox set point. This work focuses on experimental redox drug discovery targeting metastatic melanoma cells by pursuing the following specific aims: I. To identify drug-like lead compounds containing redox-directed pharmacophores for prooxidant intervention targeting melanoma in relevant models of the human disease. II. To investigate the molecular mechanism of action underlying antimelanoma activity of our lead compounds comprising Michael acceptors [cinnamaldehyde (CA) and 2,6-dichlorophenolindophenol (DCPIP)] and endoperoxides [dihydroartemesinin (DHA)]. III. To explore the therapeutic potential of drug-like electrophiles for non-melanoma indications including skin photoprotection and genotype-directed cancer chemotherapy. First, we have explored the possibility that prooxidant dietary constituents containing an electrophilic Michael acceptor pharmacophore may display chemotherapeutic activity. Focusing on the cinnamon-derived Michael acceptor CA we have demonstrated significant anti-melanoma activity of this dietary prooxidant observed in vitro and in vivo. Second, we have demonstrated that the synthetic quinoneimine and redox dye DCPIP targets human melanoma cells in vitro and in vivo. DCPIP-apoptogenicity observed in the human melanoma cell lines A375 and G361 was inversely correlated with NAD(P)H:quinone oxidoreductase (NQO1) expression levels. Efficacy against tumors with low NQO1 enzymatic activity including those displaying the human homozygous NQO1*2 missense genotype suggests feasibility of DCPIP-based genotype-directed redox intervention. Third, we demonstrated that the endoperoxide-based antimalarial DHA may serve as an experimental redox chemotherapeutic that selectively induces iron-dependent melanoma cell apoptosis without compromising viability of primary human melanocytes. Given the causative role of redox dysregulation in melanoma and the shortage of efficacious agents currently available, it seems that the emerging therapeutic potential of redox-directed chemotherapeutics for melanoma intervention deserves further evaluation.