Inadequate dietary intake of beta-carotene (and retinoids such as vitamin A) has been linked epidemiologically to increased risk of prostate cancer. Liarozole (R75251) is a novel inhibitor of intracellular retinoic acid (RA) degradation. Clinical studies now show that liarozole can significantly reduce serum prostate-specific antigen (PSA) levels and reduce tumor growth in stage D prostate cancer patients. Whilst liarozole shows promise as a clinically effective antitumoral agent, the precise molecular mechanisms of action of this promising imidazole- derived drug (as well as chemopreventative carotenoids such as beta- carotene) on the biology of prostate growth remain to be defined. This proposal has three specific objectives namely (i) to test the antiproliferative actions of liarozole and carotene derivatives in prostate cancer cells, (ii) to investigate the molecular actions of liarozole, and beta-carotene/RA upon expression of retinoid receptor (RAR, RXR) and apoptotic-associated genes (p53, bcl-2, c-myc) in the prostate. As calcium ions are involved in apoptosis, we also plan to examine the role(s) of the calcium-binding protein calbindin-D28K in the mechanisms that mediate prostate programmed cell death, (iii) in view of the fact that the thymosin beta-10 gene is preferentially expressed at high levels in numerous tumor-types, including neuroblastoma, renal cell carcinoma, thyroid, ovarian and melanocytic neoplasms as well as in prostate carcinoma, the third specific aim will be to evaluate the retinoic-acid responsive thymosin beta-10 gene as a progression marker (metastatic potential) for prostate tumors. We will execute a comparative study upon the expression of the thymosin beta-10 mRNA (and protein) in the """"""""normal"""""""", BPH and various stages of progression of prostate cancer (stages A, B, C, D, D1 & D2) and the correlated expression of the thymosin beta-10 protein with levels of prostate specific antigen (PSA). Together, these basic and clinical studies will provide more information concerning the possible molecular (apoptotic) mechanisms by which liarozole, carotene or RA prevent prostate cancer.
|Hall, A K (1996) Liarozole amplifies retinoid-induced apoptosis in human prostate cancer cells. Anticancer Drugs 7:312-20|
|Hall, A K (1995) Thymosin beta-10 accelerates apoptosis. Cell Mol Biol Res 41:167-80|
|Hall, A K (1994) Molecular interactions between G-actin, DNase I and the beta-thymosins in apoptosis: a hypothesis. Med Hypotheses 43:125-31|