Abstract
Abstract Colorectal cancer (CRC) is one of the leading causes of premature death in people worldwide. Conversion of normal colonic cells to malignant lesions requires several steps and therefore often proceeds over considerable time periods, on average, 10-15 years, thus providing a window of opportunity for effective intervention and prevention. In 2010 it was estimated that in USA alone about 150,000 people will be diagnosed with colorectal cancer and that about 50,000 people will die of the disease. Today, there is handful of truly effective drugs for colon cancer is available for the patients giving a variety of chemotherapy cocktails. Preventive therapies are promising approach for treatment of cancer, and it has a potential to be a major component of colorectal cancer control. Inducible nitric oxide synthase (iNOS) deregulation and PI3K pathways are such events occurring in colon cancer development. Currently known iNOS inhibitors, such as, S,S’-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), require high concentration for clinical efficacy in colon cancer prevention causing systemic toxicity. It is known in the literature that by replacement of sulfur with selenium in the molecule provide a higher inhibitory potency to the compound. Therefore, to develop more potent agent effective at significantly lower concentration, a novel isosteric selenium analog, namely; Se,Se’-1,4-phenylene-bis(1,2-ethanediyl)bis-isoselenourea (PBISe) was developed. Preliminary investigation from our laboratory indicates that PBISe is 25 fold more potent than PBIT in four colon cancer cell lines in MTS assay. Western blot analysis showed decrease pAkt and Akt2 levels, and downstream pPRAS40 levels, and increase in cleaved PARP an apoptosis markers that are specific for Colon cancer. The results from our investigation on maximum tolerated dose (MTD) in FBV mice and male F344 rat when feed with PBISe in a diet as well as tumorigenicity in male (heterozygous) C57BL/6J-APCmin mice and in vitro studies will be discussed. These investigations are highly significant providing insight into the chemoprevention potential and mechanisms based development of PBISe that will inhibit colon cancer. This study was supported by NCI grant CA137763 (DD). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4628. doi:10.1158/1538-7445.AM2011-4628
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