Abstract A93: Topical ISC-4 for the prevention of melanoma

Abstract

Abstract New strategies are urgently needed to prevent development of melanoma. Currently, surgical excision is the mainstay for eliminating early melanocytic lesions or preventing development of more aggressive cancer. However, use of sunscreen or body lotions containing topical agents with chemopreventive efficacy could be potentially useful for preventing cancer development. Therefore, novel topical chemopreventive agents with negligible systemic toxicity to prevent melanocytic lesion development would be a highly significant. In order to meet this unmet medical need, potent anti-melanoma agents called isoselenocyanates (ISC) have been developed from naturally occurring isothiocyanates (ITC), which are derived from plants. In these agents, sulfur has been replaced with selenium and the alkyl side chain has been lengthened from 1 or 2 to 4 or 6. The chemopreventive efficacy of ISC-4 for preventing melanoma development was evaluated in a human skin melanoma model containing early or advanced stage melanocytic lesion cell lines. Cumulative topical application of ISC-4 resulted in a >75% reduction in melanoma nodule developed in 3-D human skin reconstructs. Histological examination of drug treated skin reconstructs confirmed the chemopreventive efficacy without any obvious damage to skin cells. Furthermore, topical application of ISC-4 also effectively prevented melanoma tumor development in animals by ∼70% at 3. 83 mM with negligible toxicity compared to vehicle control. Mechanistically, ISC-4 decreased melanoma tumorigenesis causing an 3-fold increase in apoptosis by reducing pAkt3 and pPRAS40 levels and triggered caspase-3/7 activity. Furthermore, ISC-4 treatment reduced G0–G1 phase cells (30–40% decrease), and increased G2-M population by 50–60%. A 15-fold increase in the sub-G0–G1 cell population was also observed upon ISC-4 treatment compared to vehicle control treated cells. Thus, ISC-4 is a potent selenium-containing topical chemopreventive agent with significant potential to prevent melanocytic lesion development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A93.