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

Authors

  • Jiannong Li
    • Thoracic Oncology and Experimental Therapeutics ProgramH. Lee Moffitt Cancer Center and Research Institute
    • Department of Interdisciplinary OncologyUniversity of South Florida College of Medicine
  • Jean Viallet
    • GeminX, Inc
    • Thoracic Oncology and Experimental Therapeutics ProgramH. Lee Moffitt Cancer Center and Research Institute
    • Department of Interdisciplinary OncologyUniversity of South Florida College of Medicine
Original Article

DOI: 10.1007/s00280-007-0499-3

Cite this article as:
Li, J., Viallet, J. & Haura, E.B. Cancer Chemother Pharmacol (2008) 61: 525. doi:10.1007/s00280-007-0499-3

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

Copyright information

© Springer-Verlag 2007