The novel estrogen 17α-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol induces apoptosis in prostate cancer cell lines at nanomolar concentrations in vitro

Abstract

Abstract Prostate cancer remains the number one cause of noncutaneous cancer, with 220,900 new cases predicted for the year 2003 alone. Of the more promising classes of compounds studied thus far for the treatment of prostate cancer, estrogens of various types have consistently exhibited antitumor activities both in vitro and in vivo. For this reason, we have synthesized and screened a library of unique 17α/11β modified 17β-estradiol (E2) analogues designed for estrogen receptor β (ER-β) specificity and a potential for cytotoxic activity directed toward prostate cancer cells. From this library, the novel compound 17α-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (APVE2) was identified as the primary lead, found to induce a high level (>90%) of cell death through an apoptotic mechanism, with an EC50 of 1.4, 2.7, and 16 nm in the LNCaP, PC3, and DU145 cell lines, respectively. APVE2 was found to bind to ER-β, albeit weakly, with an EC50 of 250 nm and a binding activity of 6.2% relative to E2, nearly two orders of magnitude less than the concentration required to induce apoptosis. APVE2 bound preferentially to ER-β by 7-fold over ER-α, and did not induce growth in the MCF-7 cell line, thus indicating that it is not a classical ER agonist. Furthermore, the cytotoxic actions of APVE2 were not reversed by co-treatment with a 50-fold excess E2. In summary, a novel 17 modified estrogen APVE2 was identified as a lead compound, capable of inducing apoptosis in three prostate cancer cell lines at low nanomolar concentrations, through a mechanism inconsistent with an ER-mediated mechanism.