Acquired Tamoxifen Resistance and Overexpression of Anti-Apoptotic Molecules: A Potential Strategy for Overcoming Endocrine Resistance

摘要

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 chemo- and endocrine-resistance in breast cancer. we have investigated the in vitro and anti-tumor activity of (-)-gossypol, a potent small molecule inhibitor of Bcl-xL, and the potential synergistic effects of (-)-gossypol in combination with chemodrugs and Tamoxifen in breast cancer cell lines. (-)-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 by doxorubicin and docetaxel, currently used chemotherapeutic agents for breast cancer, both in vitro and in vivo. However, (-)-gossypol did not show significant enhancement of Tamoxifen activity in Er(+) breast cancer MCF-7 and T47D cells. Bcl-xL knockdown by siRNA abolished the tumorigenecity of MCF-7 cells. The data support that Bcl-xL plays a critical role in breast cancer initiation, progression and chemoresistance, but its role in endocrine 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.