Exploiting IR-Inducible NQ01 Levels Using Beta-Lapachone, A Novel Apoptotic Agent
Final rept. 1 Apr 2001-31 Mar 2004
CASE WESTERN RESERVE UNIV CLEVELAND OH
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We demonstrated that beta-lapachone beta-lap was an effective agent against human prostate cancer CaP cellstumors alone. Beta-Lap kills by targeting elevated NQ0l levels in Cap tissue. Beta-Lap radiosensitizes cells expressing this two-electron reductase inducible NQ0l levels were sufficient, but not required. Normal cells with low or no NQOl levels were spared from a-lap cytotozicity. Mechanistically, Beta-lap-induced cell responses and cell death with without IR, using cultured human CaP cells in vitro were completed. Beta-Lap alone kills by stimulating calcium-dependent PARP-l hyperactivation, resulting in AiF-mediated, caspase-independent cell death. In Aim 2, the efficacy of radiosensitization by B-lap in vivo was examined using human CaP xenografts in male nude mice. To date, we have been unsuccessful in developing LNCaP xenografts from cells expressing or lacking NQOl in athymic male mice. We are developing stable DUl45 and PC3 cells expressing siRNA to NQOl to knockdown NQOl levels. Preclinical animal studies to move Beta-lap from the bench to clinical trials against CaP are underway. Beta-Hydroxypropyl- Beta-cyclodextrin-Beta-lap HP-Beta-CD-Beta-lap complexes were developed. However, unexpected neural toxicity at high doses of Beta-lap were noted. Finally, we developed novel millirods made of PLGA-PZG polymers for use during brachytherapy, and future studies will focus on these localized treatment vehicles.
- Medicine and Medical Research