Epothilone B analogue (BMS-247550)-mediated cytotoxicity through induction of Bax conformational change in human breast cancer cells

Hirohito Yamaguchi, Michael W. Lee, Hong Gang Wang, Shanthi R. Paranawithana, Kapil N. Bhalla, Hirohito Yamaguchi, Shanthi R. Paranawithana, Kapil N. Bhalla, Hong Gang Wang, Ziwei Huang

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92 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)466-471
Number of pages6
JournalCancer Research
Volume62
Issue number2
StatePublished - Jan 15 2002

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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