Herceptin-Resistance and Overexpression of Anti-Apoptotic Molecule Bci-XL: A Potential Strategy for Overcoming Resistance to Herceptin
Annual rept. 1 Jul 2004-30 Jun 2005
MICHIGAN UNIV ANN ARBOR
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The major goal of this Concept Award project is to investigate whether a small molecule inhibitor of Bcl-xL will be able to overcome the resistance of Her-2neu- breast cancer cells to Herceptin. --gossypol showed potent anti-tumor activity to human breast cancer cell lines with high levels of Bcl-xL but has only minimal effect on human normal breast epithelial cells with low Bcl-xL. --gossypol potently enhanced growth inhibition and apoptosis induction by doxorubicin and docetaxel the currently used chemotherapeutic agents for breast cancer. However interaction of --gossypol with Herceptin activity in Her-2 breast cancer cells are still ongoing. Bcl-xL knockdown by siRNA abolished the tumorigenecity of Her-2 MCF-7 cells. The data support that Bcl-xL plays a critical role in breast cancer initiation progression and chemoresistance but its role in Herceptin resistance remains to be further elucidated. The study provide us a solid foundation to develop --gossypol as a novel molecular targeted therapy for the treatment of breast cancer with Bcl-xL overexpression.
- Medicine and Medical Research