2-Methoxyestradiol Induces G2/M Arrest and Apoptosis in Prostate Cancer

• Published in: Biochemical and biophysical research communications Vol. 285; no. 5; pp. 1259 - 1266
• Main Authors: Qadan, Laila R., Perez-Stable, Carlos M., Anderson, Curtis, D'Ippolito, Gianluca, Herron, Alan, Howard, Guy A., Roos, Bernard A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2001
• Subjects: Administration, Oral; Amino Acid Chloromethyl Ketones - pharmacology; Animals; Annexin A5 - analysis; annexins; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Caspase Inhibitors; Cell Division - drug effects; Cell Nucleus - drug effects; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Implants; Drug Resistance, Neoplasm; Enzyme Inhibitors - pharmacology; Estradiol - administration & dosage; Estradiol - analogs & derivatives; Estradiol - pharmacology; estrogens; Flow Cytometry; G2 Phase - drug effects; Humans; Male; Mice; Mice, Transgenic; Mitosis - drug effects; necrosis; Prostatic Neoplasms - chemistry; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; transgenic mice; Tumor Cells, Cultured; estrogens; annexins; flow cytometry; transgenic mice; necrosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2001.5320

Few therapeutic treatment options are available for patientssuffering 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 Gγ/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-methoxyestradiolin patients with androgen-independent prostate cancer.