iNOS/Akt Inhibotor for Colon Cancer Chemoprevention

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DESCRIPTION (provided by applicant): The Overall objective of the project is to develop mechanism based iNOS / PI3 kinase inhibitor in addition to selenium to increase potency against colon cancer prevention. Several iNOS inhibitors have been reported for prevention of cancers. One such agents, S,S'-1,4-phenylene-bis(1,2- ethanediyl)bis-isothiourea (PBIT) was effective inhibitor in vivo for colonic Aberrant crypt foci (ACF) and for prevention of esophageal cancer. Colorectal cancer (CRC) is one of the most common human malignancies in the western world, including United States. Preventive therapies are promising approach for treatment of cancer, and it has a potential to be a major component of colorectal cancer control. Due to the fact that conversion of normal colonic cells to malignant cells requires several steps and often proceeds over considerable time period, therefore there is an ample opportunity for the development of mechanism based preventive agents that may act at different stages of cancer. Recent studies have shown the importance of PI3 kinase signaling (Akt expression) and iNOS over-expressed in human colon tumors as well as in rodent models provides the basis to develop selective inhibitor of two major signaling pathways. The novel agent developed is called S,S'-1,4-phenylene-bis(1,2- ethanediyl)bis-isoselenourea (PBISe), an isosteric selenium analog of PBIT. Preliminary results from our laboratory indicate that PBISe is >25 fold more potent than PBIT in four colon cancer cell lines tested in MTS assay. Western blot analysis showed decreased pAkt and Akt2 levels, and downstream pPRAS40 levels accompanied by an increase in cleaved PARP, an apoptosis markers demonstrating decreased PI3 kinase activity upon exposure to PBISe but not PBIT. Based on hypothesis and supportive preliminary data, we want to further develop PBISe for preclinical efficacy and pharmacological studies prior to the possible use in human clinical trials. We specifically propose to investigate the pharmacokinetics, pharmacodynamics, tissue distribution, and in vivo maximum tolerated dose (MTD) of PBISe administered by intravenous injection or diet in male F344 rat model.