The long-range objective of this proposal is to enhance apoptosis in treatments for prostate cancers. The many limitations of the current treatments reflect a generally low rate of apoptosis in these tumors. Studies with new clinical DNA reactive drugs, hydroxymethylacylfulvene (HMAF) and oxaliplatin, demonstrated their potent pro-apoptotic and cytotoxic properties in prostate cancer lines. In contrast to the sensitivity of tumor cells, normal cells have protective mechanisms preventing apoptosis by HMAF. Both HMAF and oxaliplatin are effective in enhancing the effects of ionizing radiation in prostate cancer cells. Recent studies verified that DNA is an important target for these drugs. However, in addition to DNA damage, these drugs also cause protein damage. These and other findings led to a proposal that protein damage and resulting distortion of redox homeostasis contribute to apoptosis by these agents. This challenges a long standing notion that protein binding of nominally DNA-reactive drugs is merely a detoxification event. Whereas DNA damage initiates damage signaling and the apoptotic process, protein damage may facilitate apoptosis execution by pro-oxidative changes of cellular milieu. Such a dual action may be the basis of the potent pro-apoptotic properties of these and other drugs which react with both DNA and proteins. The proposed studies with HMAF and oxaliplatin will explore the pro-apoptotic activity and mechanism of these drugs. Specifically, they will: (1) Determine the potential of the drugs to induce apoptosis and inhibit cell growth alone and in combination with gamma-radiation, (2) Identify and characterize redox-related stages in the execution of apoptosis induced by HMAF and oxaliplatin in prostate cancer cells, and (3) Test the relative contribution of protein damage vs. DNA damage to apoptosis by these agents. These studies will help to optimize the clinical use of these drugs alone and in combination with gamma-radiation. Studies to uncover the potentially novel aspects of drug-induced apoptosis will provide leads for targeting apoptosis in prostate cancer with DNA- and protein-damaging agents in general.
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