1.Targeting Akt3 signaling in malignant melanoma using isoselenocyanates.
Sharma A1, Sharma AK, Madhunapantula SV, Desai D, Huh SJ, Mosca P, Amin S, Robertson GP. Clin Cancer Res. 2009 Mar 1;15(5):1674-85. doi: 10.1158/1078-0432.CCR-08-2214. Epub 2009 Feb 10.
PURPOSE: Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas because its activity is increased in approximately 70% of tumors, decreasing apoptosis in order to promote tumorigenesis.
2.Melanoma chemoprevention in skin reconstructs and mouse xenografts using isoselenocyanate-4.
Nguyen N1, Sharma A, Nguyen N, Sharma AK, Desai D, Huh SJ, Amin S, Meyers C, Robertson GP. Cancer Prev Res (Phila). 2011 Feb;4(2):248-58. doi: 10.1158/1940-6207.CAPR-10-0106. Epub 2010 Nov 19.
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.
3.Phenylbutyl isoselenocyanate modulates phase I and II enzymes and inhibits 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone-induced DNA adducts in mice.
Crampsie MA1, Jones N, Das A, Aliaga C, Desai D, Lazarus P, Amin S, Sharma AK. Cancer Prev Res (Phila). 2011 Nov;4(11):1884-94. doi: 10.1158/1940-6207.CAPR-11-0221. Epub 2011 Jul 27.
Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed on the basis of naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In this study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 μmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time-dependent inhibition of microsomal cytochrome P450 (Cyp450) activity and delayed increases in phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity.
4.The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model.
Sharma AK1, Kline CL, Berg A, Amin S, Irby RB. Clin Cancer Res. 2011 Jul 1;17(13):4474-83. doi: 10.1158/1078-0432.CCR-10-2370. Epub 2011 May 9.
PURPOSE: Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4-overexpressing colon cancer cells responded more readily to 5-fluorouracil (5-FU) than their wild-type counterparts. In this study we investigated (i) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and (ii) bystander effect of Par-4-overexpressing cells on wild-type tumor growth.