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. 2008 Mar;61(3):525-34. doi: 10.1007/s00280-007-0499-3. Epub 2007 May 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • ErbB Receptors / antagonists & inhibitors
  • Humans
  • Immunoprecipitation
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Neoplasm Proteins / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Pyrroles / pharmacology*
  • Tetrazolium Salts
  • Thiazoles

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Tetrazolium Salts
  • Thiazoles
  • ErbB Receptors
  • thiazolyl blue
  • Cisplatin
  • obatoclax