Melanoma Chemoprevention in Skin Reconstructs and Mouse Xenografts Using Isoselenocyanate-4

Abstract

Melanoma incidence and mortality rates continue to increase despite the use of sunscreen as well as screening programs for early surgical excision of premalignant lesions. The steady increase in melanoma incidence suggests that additional preventive approaches are needed to augment these existing strategies. One unexplored area involves targeting genes whose deregulation promotes disease development to prevent melanoma. The Akt3 signaling pathway is one key signaling cascade that plays a central role by deregulating apoptosis to promote development of approximately 70% of melanomas. Isoselenocyanate-4 (ISC-4), derived from isothiocyanates by increasing the alkyl chain length and replacing sulfur with selenium, has been developed to target this important signaling pathway in melanomas; however, its chemopreventive potential is unknown. In this study, the chemopreventive efficacy of topical ISC-4 was evaluated in a laboratory-generated human skin melanoma model containing early melanocytic lesion or advanced stage melanoma cell lines and in animals containing invasive xenografted human melanoma. Repeated topical application of ISC-4 reduced tumor cell expansion in the skin model by 80% to 90% and decreased tumor development in animals by approximately 80%. Histologic examination of ISC-4-treated skin showed no obvious damage to skin cells or skin morphology, and treated animals did not exhibit markers indicative of major organ-related toxicity. Mechanistically, ISC-4 prevented melanoma by decreasing Akt3 signaling that lead to a 3-fold increase in apoptosis rates. Thus, topical ISC-4 can delay or slow down melanocytic lesion or melanoma development in preclinical models and could impact melanoma incidence rates if similar results are observed in humans. Cancer Prev Res; 4(2); 248-58. Ó2010 AACR.

Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway

“…Epidemiologic studies have reported an inverse association between the nutritional selenium status and cancer risk 42 , suggesting that a relatively low Se status may be among the determinants of cancer risk. We have also shown selenium compounds to be effective in inhibiting tumor growth in melanoma 31–34 and colon 43 xenograft models. Specifically, several synthetic alkyl and aryl selenocyanates have been evaluated for anticarcinogenicity in animal models.…”

Selenium-containing histone deacetylase inhibitors for melanoma management

“…40,41 Despite some success, additional approaches are needed, which might involve preventing melanocytic lesions from developing or progressing past its earliest stages, using agents that could be added to creams, lotions or sunblocks. 42 Addition of PCP-SeCN and B(PCP)-2Se to these topical agents could be one approach to prevent melanoma. SAHA is approved by the FDA but is only marginally effective for treating solid tumors.…”

“…42,46 Low selenium levels have also been reported in the serum of patients suffering from cancers including melanoma, which could be mitigated by the selenium released from these agents. 47,48 Since incorporation of selenium in a drug can increase its efficacy for killing melanoma cells by inhibiting PI3 kinase pathway signaling, similar modifications were predicted to enhance the therapeutic potential of SAHA.…”

The Akt signaling pathway

“…93,100,101 Mechanistically, ISC-4 has been shown to inhibit Akt3 signaling in melanomas and induce apoptotic cell death.…”