title: 2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer.
abstract: Few therapeutic treatment options are available for patients suffering from metastatic androgen-independent prostate cancer. We investigated the ability of the estrogen metabolite 2-methoxyestradiol to inhibit the proliferation of a variety of human prostate cancer cell lines in vitro and to inhibit the growth of androgen-independent prostate cancer in a transgenic mouse model in vivo. Our results showed that 2-methoxyestradiol is a powerful growth inhibitor of LNCaP, DU 145, PC-3, and ALVA-31 prostate cancer cells. Cell flow cytometry of 2-methoxyestradiol-treated DU 145 cells showed a marked accumulation of cells in the G2/M phase of the cell cycle and an increase in the sub-G1 fraction (apoptotic). In addition, staining for annexin V, changes in nuclear morphology, and inhibition of caspase activity support a role for apoptosis. More importantly, we showed that 2-methoxyestradiol inhibits prostate tumor progression in the Ggamma/T-15 transgenic mouse model of androgen-independent prostate cancer without toxic side effects. These results in cell culture and an animal model support investigations into the clinical use of 2-methoxyestradiol in patients with androgen-independent prostate cancer.
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service, VA Medical Center, Miami, Florida 33125, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Qadan
authors.forename: C M
authors.initials: CM
authors.lastname: Perez-Stable
authors.forename: C
authors.initials: C
authors.lastname: Anderson
authors.forename: G
authors.initials: G
authors.lastname: D'Ippolito
authors.forename: A
authors.initials: A
authors.lastname: Herron
authors.forename: G A
authors.initials: GA
authors.lastname: Howard
authors.forename: B A
authors.initials: BA
authors.lastname: Roos
mesh_terms: D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004343:Drug Implants; D004791:Enzyme Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D004958:Estradiol; D000077584:2-Methoxyestradiol