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Experimental Therapeutics |
Drug Discovery Program [H. Y., M. W. L., H-G. W.] and Clinical Investigations Program [S. R. P., K. N. B.], H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612; Departments of Interdisciplinary Oncology [H. Y., S. R. P., K. N. B., H-G. W.] and Pharmacology [M. W. L., H-G. W.], University of South Florida, College of Medicine, Tampa, Florida 33612; and Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 [Z. H.]
Epothilone B is a novel nontaxane antimicrotubule agent that is active even against paclitaxel (Taxol)-resistant cancer cells. The present study further explores the mechanisms underlying epothilone B-mediated cytotoxicity in human breast cancer cells. We show that BMS-247550 (EpoB), a novel epothilone B analogue, induces cell cycle arrest at the G2-M phase transition and subsequent apoptotic cell death of MDA-MB-468 (468) cells. Treating cells with EpoB triggers a conformational change in the Bax protein and its translocation from the cytosol to the mitochondria, which is accompanied by cytochrome c release from the inter-membrane space of mitochondria into the cytosol. Overexpression of Bcl-2 delays Bax conformational change, cytochrome c release, and apoptosis induced by EpoB. Conversely, the Bcl-2 antagonist Bak-BH3 peptide or HA14-1 compound abrogates the antiapoptotic effects of Bcl-2 and enhances apoptosis of 468 cells pretreated with EpoB (to induce mitotic arrest). In synchronized 468 cells, EpoB is more potent in inducing Bax conformational change and apoptosis at G2-M phase compared with G1-S phase of the cell cycle. Taken together, these findings demonstrate that EpoB induces apoptosis through a Bcl-2-suppressible pathway that controls a conformational change of the proapoptotic Bax protein. The enhanced cytotoxicity of EpoB by blocking Bcl-2 at mitochondria implies a potential application of the combination of EpoB and Bcl-2 antagonists in the treatment of human breast cancer.
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