Therapeutics of XIAP Degradation by Zinc Chelators

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DESCRIPTION (provided by applicant): Androgen-independent prostate cancer is associated with an extremely poor treatment response and a limited prognosis using current treatment modalities. Therefore, the development of new therapeutic strategies for advanced prostate cancer represents a goal with enormous clinical and scientific merit. Findings from our laboratory indicate that treatment of prostate cancer cells with the zinc chelating agent N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces selective down-regulation of the X-linked inhibitor of apoptosis protein (XIAP) and sensitizes cancer cells to death ligand-mediated apoptosis. We have also observed a significant reduction of XIAP levels in cells treated with protoporphyrin IX, a naturally occurring chelating molecule. Moreover, the intracellular accumulation of protoporphyrin IX, after exogenous administration of its precursor 5-ALA, coincides with reduced XIAP expression in PC-3 prostate cancer cells and an increased sensitivity to TRAIL-mediated apoptosis. The preferential accumulation of protoporphyrin IX and its derivatives in neoplastic lesions is well established and has been extensively employed for photodetection and photodynamic therapy in various malignancies. We hypothesize that displacement of zinc sensitizes malignant cells to cytotoxic agents via down-regulation of XIAP and, therefore, zinc chelation might represent a novel mechanism for prostate cancer therapy. Importantly, our data and the results of others demonstrate that the depletion of XIAP by itself is sufficient to reverse resistance to TRAIL-mediated apoptosis in cancer cells. To test our hypothesis and to evaluate the therapeutic uses of zinc chelating agents in prostate cancer, we propose the following Specific Aims: Aim 1: To identify 5-ALA derivatives with improved capability of sensitizing prostate cancer cells to cytotoxic agents in vitro; Aim 2: To examine the oral bioavailability of 5-ALA esterified derivatives and the tissue distribution of 5-ALA induced PPIX in a xenograft model of prostate cancer; Aim 3: To examine the in vivo anti-tumor efficacy and toxicity of 5-ALA derivatives. XIAP levels are elevated in many cancer cell lines, and suppression of XIAP protein levels can sensitize cancer cells to cytotoxic drugs. This makes XIAP an attractive target for the design of novel anti-tumor agents.