A Topical Zinc Ionophore Blocks Tumorigenic Progression in UV‐exposed SKH‐1 High‐risk Mouse Skin

Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States representing a considerable public health burden. Pharmacological suppression of skin photocarcinogenesis has shown promise in preclinical and clinical studies, but more efficacious photochemopreventive agents are needed. Here, we tested feasibility of harnessing pharmacological disruption of intracellular zinc homeostasis for photochemoprevention in vitro and in vivo. Employing the zinc ionophore and FDA-approved microbicidal agent zinc pyrithione (ZnPT), used worldwide in over-the-counter (OTC) topical consumer products, we first demonstrated feasibility of achieving ZnPT-based intracellular Zn2+ overload in cultured malignant keratinocytes (HaCaT-ras II-4; SCC-25) employing membrane-permeable fluorescent probes. Zinc overload was accompanied by induction of intracellular oxidative stress, associated with mitochondrial superoxide release as substantiated by MitoSOX Red™ fluorescence microscopy. ZnPT-induced cell death observable in malignant keratinocytes was preceded by induction of metal (MT2A), proteotoxic (HSPA6, HSPA1A, DDIT3, HMOX1) and genotoxic stress response (GADD45A, XRCC2) gene expression at the mRNA and protein levels. Comet analysis revealed introduction of formamidopyrimidine-DNA glycosylase (Fpg)-sensitive oxidative DNA lesions. In a photocarcinogenesis model (UV-exposed SKH-1 high-risk mouse skin), topical ZnPT administration post-UV caused epidermal zinc overload and stress response gene expression with pronounced blockade of tumorigenesis. Taken together, these data suggest feasibility of repurposing a topical OTC drug for zinc-directed photochemoprevention of solar UV-induced NMSC.