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.
| Liang, Huiyun; Salinas, Richard A; Leal, Belinda Z et al. (2004) Caspase-mediated apoptosis and caspase-independent cell death induced by irofulven in prostate cancer cells. Mol Cancer Ther 3:1385-96 |
| Woynarowski, Jan M; Woynarowska, Barbara A; Trevino, Alex V et al. (2004) Cell cycle effects and induction of premitotic apoptosis by irofulven in synchronized cancer cells. Cancer Biol Ther 3:1137-42; discussion 1143-4 |
| Herzig, Maryanne C S; Trevino, Alex V; Liang, Huiyun et al. (2003) Apoptosis induction by the dual-action DNA- and protein-reactive antitumor drug irofulven is largely Bcl-2-independent. Biochem Pharmacol 65:503-13 |
| Faivre, Sandrine; Chan, Denise; Salinas, Richard et al. (2003) DNA strand breaks and apoptosis induced by oxaliplatin in cancer cells. Biochem Pharmacol 66:225-37 |
| Herzig, Maryanne C S; Liang, Huiyun; Johnson, Anne E et al. (2002) Irofulven induces apoptosis in breast cancer cells regardless of caspase-3 status. Breast Cancer Res Treat 71:133-43 |
| Woynarowska, Barbara A; Woynarowski, Jan M (2002) Preferential targeting of apoptosis in tumor versus normal cells. Biochim Biophys Acta 1587:309-17 |
| Raymond, Eric; Faivre, Sandrine; Chaney, Stephen et al. (2002) Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 1:227-35 |
| Woynarowska BAHigdon, A L; Munoz, R M; Bushong, P et al. (2001) Changes in prostate-specific antigen (PSA) level correlate with growth inhibition of prostate cancer cells treated in vitro with a novel anticancer drug, irofulven. Invest New Drugs 19:283-91 |
| Faderl, S; Estrov, Z; Kantarjian, H M et al. (2001) WP744, a novel anthracycline with enhanced proapoptotic and antileukemic activity. Anticancer Res 21:3777-84 |
| Woynarowski, J M; Faivre, S; Herzig, M C et al. (2000) Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol 58:920-7 |
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