Original Article

Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 3, pp 525-534

A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells

  • Jiannong LiAffiliated withThoracic Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Interdisciplinary Oncology, University of South Florida College of Medicine
  • , Jean VialletAffiliated withGeminX, Inc
  • , Eric B. HauraAffiliated withThoracic Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Interdisciplinary Oncology, University of South Florida College of Medicine Email author 

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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.

Keywords

Mcl-1 Bcl-2 GX15-070 Lung cancer Apoptosis Chemotherapy