The Role of Acetyl Zingerone and Its Derivatives in Inhibiting UV-Induced, Incident, and Delayed Cyclobutane Pyrimidine Dimers

Author:

Srivastava Jyoti1,Young Montana M.1,Yadav Vipin Kumar1ORCID,Phadatare Pravin R.1,Meyer Thomas A.2,Chaudhuri Ratan K.2,Premi Sanjay1ORCID

Affiliation:

1. Tumor Biology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA

2. SYTHEON, 10 Waterview Blvd, Parsippany, NJ 07054, USA

Abstract

Cyclobutane pyrimidine dimers (CPDs) are ultraviolet radiation (UV)-induced carcinogenic DNA photoproducts that lead to UV signature mutations in melanoma. Previously, we discovered that, in addition to their incident formation (iCPDs), UV exposure induces melanin chemiexcitation (MeCh), where UV generates peroxynitrite (ONOO−), which oxidizes melanin into melanin-carbonyls (MCs) in their excited triplet state. Chronic MeCh and energy transfer by MCs to DNA generates CPDs for several hours after UV exposure ends (dark CPD, dCPDs). We hypothesized that MeCh and the resulting dCPDs can be inhibited using MeCh inhibitors, and MC and ONOO− scavengers. Here, we investigated the efficacy of Acetyl Zingerone (AZ), a plant-based phenolic alkanone, and its chemical analogs in inhibiting iCPDs and dCPDs in skin fibroblasts, keratinocytes, and isogenic pigmented and albino melanocytes. While AZ and its methoxy analog, 3-(4-Methoxy-benzyl)-Pentane-2,4-dione (MBPD) completely inhibited the dCPDs, MBPD also inhibited ~50% of iCPDs. This suggests the inhibition of ~80% of total CPDs at any time point post UV exposure by MBPD, which is markedly significant. MBPD downregulated melanin synthesis, which is indispensable for dCPD generation, but this did not occur with AZ. Meanwhile, AZ and MBPD both upregulated the expression of nucleotide excision repair (NER) pathways genes including Xpa, Xpc, and Mitf. AZ and its analogs were non-toxic to the skin cells and did not act as photosensitizers. We propose that AZ and MBPD represent “next-generation skin care additives” that are safe and effective for use not only in sunscreens but also in other specialized clinical applications owing to their extremely high efficacy in blocking both iCPDs and dCPDs.

Funder

Moffitt Cancer Center (MCC) and Research Institute

Sytheon Pvt. Ltd.

“Miles for Moffitt” movement

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

Reference45 articles.

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