2017/05/15 by Rebecca Justiniano, Jessica Perer, Anh Hua +4 · 6 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Skin Protection and Aging #melanin and skin pigmentation #Retinoids in leukemia and cellular processes
paper · doi:10.1111/php.12794
Abstract 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 Zn PT ‐based intracellular Zn 2+ 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 Mito SOX Red™ fluorescence microscopy. Zn PT ‐induced cell death observable in malignant keratinocytes was preceded by induction of metal ( MT 2A ), proteotoxic ( HSPA 6 , HSPA 1A, DDIT 3, HMOX 1 ) and genotoxic stress response ( GADD 45A , XRCC 2 ) 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 Zn PT 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 .