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The alarming increase in prostate cancer incidence and its ranking as the second leading cause of cancer-related deaths in men lends an urgency to find new ways for its management. 2-Methoxyestradiol (2-ME) is an endogenous non-toxic metabolic byproduct of estrogens that is present in human urine and blood and has been shown to inhibit the growth of different cancer cells including prostate via apoptosis. 2-ME is in clinical trial for the treatment of hormone refractory prostate cancer (HRPC). However, the chemopreventive potential of 2-ME in the management of prostate cancer before the development of clinically significant metastatic disease remains unknown. We evaluated the potential of 2-ME in suppressing the development of prostate tumors in the TRAMP (transgenic adenocarcinoma of mouse prostate) model. Feeding 8 wk old TRAMP mice on a diet containing 2-ME (50 mg/kg) for 16 wks showed a 33% reduction in the wet weight of the prostate. Histological analysis indicates that the glands from these animals are composed of columnar epithelium with round to oval nuclei with no indication of neoplasia in contrast to prostates from control animals that displayed epithelial proliferation in a characteristic cribriform pattern with hyperchromatic nuclei; mitotic figures and apoptotic bodies. We have also identified through DNA array analysis that TNF-α stimulated gene-6 (TSG-6) was induced by 7-fold in response to 2-ME treatment of LNCaP cells. We have confirmed using immunocytochemistry and immunohistochemistry that TSG-6 was undetectable in prostate cancer cell lines or in prostate tumor from TRAMP mice but became detectable in 2-ME treated cells or in prostate tissue from 2-ME fed TRAMP mice. Overexpression of TSG-6 but not antisense TSG-6 inhibited the invasiveness of PC-3 cells significantly in tumor invasion assay. Further combining 2-ME with eugenol (4-allyl-2-methoxyphenol) exhibited synergistic growth inhibitory activity. Overexpression of antiapoptotic protein Bcl-2 did not affect this synergistic growth inhibitory activity. Thus combination of these agents may sensitize the prostate cancer cells to apoptosis in the presence of Bcl-2. Combining these agents may allow ameliorating any adverse effects of either 2-ME or eugenol alone by reducing their individual concentrations on PCA prevention efforts should these two agents be developed for human use. Since defects in the Bcl-2 regulated apoptotic signaling has been implicated in the development of resistance to chemotherapy or radiotherapy, our data showing induction of apoptosis by combining 2-ME with Eugenol in Bcl-2 overexpressing transfectants warrants further studies not only in prostate but in other models. Supported in part through American Cancer Society (RSG-04-169-01CNE) and National Cancer Institute (CA 98744).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]