| Title | Epothilone B analogue (BMS-247550)-mediated cytotoxicity through induction of Bax conformational change in human breast cancer cells. | | Author(s) | Yamaguchi H, Paranawithana SR, Lee MW, Huang Z, Bhalla KN, Wang HG | | Institution | Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. | | Source | Cancer Res 2002 Jan 15; 62(2):466-71. | | MeSH | Antineoplastic Agents
Apoptosis
Breast Neoplasms
Epothilones
Epoxy Compounds
G2 Phase
Humans
Mitochondria
Mitosis
Protein Conformation
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
Thiazoles
Tumor Cells, Cultured
bcl-2-Associated X Protein
| | Abstract | 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 G(2)-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 G(2)-M phase compared with G(1)-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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, U.S. Gov't, P.H.S.
| | PubMed ID | 11809697 |
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