Abstract
Purpose
Overexpression of Bcl-2 family members as well as deregulated apoptosis pathways are known hallmarks of lung cancer. Non-small cell lung cancer (NSCLC) cells are typically resistant to cytotoxic chemotherapy and approaches that alter the balance between pro-survival and pro-death Bcl-2 family members have shown promise in preclinical models of NSCLC.
Methods
Here we evaluated the effects of a novel pan-Bcl-2 inhibitor GX15-070 on NSCLC survival and when combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as well as traditional cytotoxic agents. GX15-070 is a small molecule agent that binds anti-apoptotic Bcl-2 proteins and interferes with their ability to interact with pro-apoptotic proteins. We evaluated the effect of GX15-070 and correlated the effect on EGFR status as well as Bcl-2 family protein expression.
Results
We show that GX15-070 can disrupt Mcl-1:Bak interactions in lung cancer cells. We identified differential sensitivity of a panel of lung cancer cells to GX15-070 and no clear relationship existed between EGFR status or Bcl-2 family protein expression and sensitivity to GX15-070. GX15-070 could induce apoptosis in a subset of lung cancer cell lines and this correlated with the effects on cell viability. GX15-070 combined with gefitinib was synergistic in a cell line dependent on EGFR for survival but GX15-070 could not reverse resistance to gefitinib in cell lines not dependent on EGFR for survival. Finally, we observed synergy between GX15-070 and cisplatin in NSCLC cells.
Conclusions
Based on these results, GX15-070 can trigger apoptosis in NSCLC cells and can enhance chemotherapy-induced death. These data suggest that clinical trials with GX15-070 in combination with cytotoxic chemotherapy are indicated.
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Acknowledgments
We thank Dr Mark Watson (GeminX Biotechnologies Inc., Montreal, QC, Canada) for help with coimmunoprecipitation assays and Drs Pasi Janne (Dana Farber, Boston, MA, USA), Jon Kurie (MD Anderson, Houston, TX, USA), and Jeffrey Settleman (Massachusetts General Hospital Cancer Center, Boston, MA, USA) for providing cell lines. We thank Drs Warren Fiskus and Kapil Bhalla (Medical College of Georgia Cancer Center, Augusta, GA, USA) for help with synergy analysis, and Tiffany Dyn for administrative assistance. This work has been supported in part by the Molecular Imaging Core, Molecular Biology and Sequencing Core, and the Flow Cytometry Core at the H. Lee Moffitt Cancer Center & Research Institute. This work was partially funded by the H. Lee Moffitt Cancer Center & Research Institute.
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Li, J., Viallet, J. & Haura, E.B. A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol 61, 525–534 (2008). https://doi.org/10.1007/s00280-007-0499-3
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DOI: https://doi.org/10.1007/s00280-007-0499-3