title: Low dose combinations of 2-methoxyestradiol and docetaxel block prostate cancer cells in mitosis and increase apoptosis.
abstract: Clinical trials have shown that chemotherapy with docetaxel (Doc) combined with prednisone can improve survival of patients with androgen-independent prostate cancer (AI-PC). It is likely that the combination of Doc with other novel agents would also improve the survival of AI-PC patients. We investigated whether the combination of Doc and 2-methoxyestradiol (2ME2), an endogenous metabolite of estradiol promising for cancer therapy, can increase apoptotic cell death in prostate cancer cells. Low concentration 2ME2 (0.5-1 microM)+Doc (0.05-0.1 nM) combinations inhibit cell growth, increase G2/M cell cycle arrest, and increase apoptosis more effectively than the single concentrations in a variety of human AI-PC cells. Effects on apoptosis were associated with an increase in p53 protein and a decrease in cyclin A-dependent kinase activity. We then investigated whether the combination of 2ME2+Doc can increase apoptotic cell death and inhibit the growth of prostate tumors in the FG/Tag transgenic mouse model of AI-PC. Doses of 2ME2 and Doc that increase mitotic cell cycle arrest result in an increase in apoptosis and lower primary prostate tumor weights in FG/Tag mice. High dose 2ME2+Doc combinations did not increase G2/M cell cycle arrest or apoptosis in AI-PC cell lines and in the FG/Tag mice more than the single drugs. Overall, our data indicate that low dose 2ME2+Doc combinations may provide a treatment strategy that can improve therapeutic efficacy against AI-PC while reducing toxicity often seen in patients treated with Doc.
authors.affiliation: Division of Gerontology & Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Teresita
authors.initials: T
authors.lastname: Reiner
authors.forename: Alicia
authors.initials: A
authors.lastname: de las Pozas
authors.forename: Lourdes A
authors.initials: LA
authors.lastname: Gomez
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Stable
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering; D043823:Taxoids / Q000008:administration & dosage; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; D004958:Estradiol; D000077584:2-Methoxyestradiol