title: 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.
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nguyen
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.forename: Nhung
authors.initials: N
authors.lastname: Nguyen
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Huh
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Craig
authors.initials: C
authors.lastname: Meyers
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D003485:Cyanates / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000502:physiology; D007124:Immunoenzyme Techniques; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018036:Selenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003485:Cyanates; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D018036:Selenium Compounds; C090140:Whn protein; C053721:selenocyanic acid; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt