Vitamin A derivatives such as retinoids are known to inhibit cell proliferation and induce cellular differentiation/apoptosis in various tumor cells. Although many retinoids have been limited due to their severe adverse effects, but 9cUAB30, a highly selective novel retinoid X receptors (RXR)-agonist has been shown an effective anti-carcinogenic activity. Here, we demonstrated the chemopreventive and chemotherapeutic efficacy of 9cUAB30 in UVB-induced photocarcinogenesis in Ptch+/-/SKH-1 murine model, which develops both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Both topical and systemic application to 9cUAB30 significantly reduced UVB-induced skin photocarcinogenesis in terms of tumor number and tumor volume. 9cUAB30 reduced UVB-induced skin hyperplasia, proliferation, and enhanced differentiation of suprabasal epidermal keratinocytes. Induction of apoptosis was also noted in these neoplastic lesions treated with this retinoid. 9cUAB30 was almost equally potent in the inhibition of either UVB-induced skin BCCs or SCCs in Ptch+/-/SKH-1 mice. 9cUAB30-treated residual tumors were manifesting reduced epithelial-mesenchymal transition (EMT) progression with a less aggressive tumor phenotype, which was associated with the enhanced expression of E-cadherin and reduced expression of N-cadherin, Fibronectin, Snail and Twist. 9cUAB30-mediated therapeutic intervention against these tumors was also involved induction of extensive DNA double strand breaks (DSBs) characterized by the enhanced phosphorylation of H2AX. This DNA damage response was unique to 9cUAB30 compare to other known RXR inhibitors such as Bexarotene. It was also independent of reactive oxygen species (ROS) production as ROS scavenger namely, N-acetyl cysteine did not effectively block it. However, 9cUAB30 provoked DNA damage response signaling was associated with the enhanced phosphorylation and activation of ATM, Rad50, ATR, Chk1, and Chk2. In summary, these data demonstrate that 9cUAB30 is a novel cancer chemopreventive agent for UVB-induced skin neoplasm and acts by invoking extensive DDSBs similar to those caused by chemotherapeutic drug like cisplatin.
Citation Format: Sandeep C. Chaudhary, Mahendra P. Kashyap, Gloria Nguyen, Craig A. Elmets, Mohammad Athar. 9cis-retinoid UAB30 manifests potent chemopreventive effects in a murine model of UVB-induced basal cell and squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-170.