Introduction: Zinc accumulates at levels 10-fold higher in the prostate than other soft tissues and this metal is implicated in prostate cancer (PCa) pathogenesis. Prostatic lesions have 6-fold lower concentrations of zinc than normal adjacent prostate tissue. Zinc levels are even lower in normal and malignant prostate tissue from African American (AA) men, who are 1.5 times more likely to develop prostate cancer than their Caucasian (Cauc) counterparts, thus highlighting the associative that that zinc could have in prostate cancer carcinogenesis. PAC-1 is a chemotherapeutic agent that induces cell death via zinc sequestration by activation of pro-caspase 3, which is a major player in cell death. We hypothesized that the low zinc levels in prostate cancer cells will cause the cells to be uniquely sensitive to cell death by PAC-1. Secondarily we hypothesized that AA patients, who have lower zinc in the prostate, may have enhanced response to PAC-1. Methods: PAC-1 cytotoxicity was investigated in LNCaP, PC-3, 957e/hTERT (immortalized normal primary cell line) and patient-derived normal and cancer primary epithelial cells (PrE) by treatment with 100, 50, 25,10,1, 0 micromolar concentrations of PAC-1 and PAC-1 analogs. Cell death was analyzed via the MTS colorimetric assay. Results and conclusion: Normal and cancer prostate cells are sensitive to PAC-1 and even more sensitive to PAC-1 analogs. PAC-1 was growth inhibitory and induced cell death at higher concentrations. Ongoing studies will examine zinc-dependency of PAC-1-induced death. PAC-1 and its analogs-induced cell death and caspase-3 activation will be measured in zinc-depleted, zinc sufficient and zinc-excess media. Studies will also determine PAC-1 cytotoxicity in normal and cancer prostatic epithelial cells. PAC-1 cytotoxicity levels in patient-matched prostate cancer cells (PrCa) from AA and Cauc men will also be studied to interrogate the disparate role of zinc in regards to sensitivity to PAC-1. These results may be translated to the clinic since a derivative of PAC-1 (S-PAC-1) has been shown to have positive effects in a Phase I clinical trial in pet dogs with lymphoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3801. doi:1538-7445.AM2012-3801