Role of Nitric Oxide as a Chemosensitizer in Prostate Cancer

Abstract : Most patients who die of prostate cancer do so because of therapy failure. Regional hypoxia is a prevalent feature of prostate carcinomas and hypoxia contributes to chemoresistance in various types of cancer. Thanks to the funding provided by the US Army Medical Research and Material Command (Award no. DAMDl7-03-l-OO7O), we have shown that hypoxia increases resistance to more than one class of chemotherapeutic agents in human and rodent prostate cancer cells. Specifically, our studies reveal that incubation of human (PC-3 and DU-l45) as well as mouse (TRAMP-C2) prostatic adenocarcinoma cells under hypoxia (O.5%02) significantly increases their resistance to chemotherapeutic drugs that exert their cytotoxic effects via different mechanisms, i.e. doxorubicin and paclitaxel. Moreover, we have also demonstrated that the effect of hypoxia on chemoresistance of prostate cancer cells can be prevented by very low concentrations of nitric oxide mimetic agents (Task 1). As initially proposed in the Statement of Work, we were able to accomplish these objectives within the first 12 months of funding. These findings suggest that it may be feasible to use NO mimetics as adjuvants to chemotherapy in prostate cancer patients.