2-Methoxyestradiol and paclitaxel have similar effects on the cell cycle and induction of apoptosis in prostate cancer cells.
2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with promise for cancer chemotherapy, including advanced prostate cancer. We have focused on events related to cell cycle arrest (G1 and G2/M) and induction of apoptosis in human prostate cancer cells. Treatment with 2-ME increased cyclin B1 protein and its associated kinase activity followed by later inhibition of cyclin A-dependent kinase activity and induction of apoptosis. Similar results were obtained with paclitaxel (taxol), a clinically relevant agent used to treat advanced prostate cancer. Cyclin-dependent kinase inhibitors prevented 2-ME and paclitaxel-mediated increase in cyclin B1-dependent kinase activity and blocked induction of apoptosis. Reduction of X-linked inhibitor of apoptosis (XIAP) protein by 2-ME and paclitaxel correlated with increased apoptosis. Lower doses of 2-ME and paclitaxel resulted in G1 (but not G2/M) cell cycle arrest in the p53 wild type LNCaP cell line, but with minimal induction of apoptosis. We suggest that 2-ME and paclitaxel-mediated induction of apoptosis in prostate cancer cells requires activation of cyclin B1-dependent kinase that arrests cells in G2/M and subsequently leads to the induction of apoptotic cell death.
Perez-Stable
Carlos
C
Geriatric Research, Education, and Clinical Center and Research Service, Veterans Affairs Medical Center, GRECC (11-GRC), 1201 NW 16 Street, Miami, FL 33125, USA. cperez@med.miami.edu
D000077584:2-Methoxyestradiol; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D056744:Cyclin B1; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D056744:Cyclin B1; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel