Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer

Mol Cancer. 2013 Mar 2;12:16. doi: 10.1186/1476-4598-12-16.

Abstract

Background: New therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies.

Methods: We explored the combination of ABT-737 and chloroquine, an inhibitor of autophagy, in preclinical models of SCLC. These included cell culture analyses of viability and of autophagic and apoptotic pathway induction, as well as in vivo analyses of efficacy in multiple xenograft models.

Results: Combination treatment of SCLC lines with ABT-737 and chloroquine decreased viability and increased caspase-3 activation over treatment with either single agent. ABT-737 induced several hallmarks of autophagy. However, knockdown of beclin-1, a key regulator of entry into autophagy, diminished the efficacy of ABT-737, suggesting either that the effects of chloroquine were nonspecific or that induction but not completion of autophagy is necessary for the combined effect of ABT-737 and chloroquine. ABT-737 and chloroquine in SCLC cell lines downregulated Mcl-1 and upregulated NOXA, both of which may promote apoptosis. Treatment of tumor-bearing mice demonstrated that chloroquine could enhance ABT-737-mediated tumor growth inhibition against NCI-H209 xenografts, but did not alter ABT-737 response in three primary patient-derived xenograft models.

Conclusion: These data suggest that although ABT-737 can induce autophagy in SCLC, autophagic inhibition by choroquine does not markedly alter in vivo response to ABT-737 in relevant preclinical models, arguing against this as a treatment strategy for SCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy
  • Beclin-1
  • Biphenyl Compounds / administration & dosage
  • Cell Proliferation / drug effects
  • Cell Survival
  • Chloroquine / administration & dosage
  • Drug Resistance, Neoplasm
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Nitrophenols / administration & dosage
  • Piperazines / administration & dosage
  • RNA, Small Interfering / genetics
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / pathology
  • Sulfonamides / administration & dosage
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • ABT-737
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Biphenyl Compounds
  • Membrane Proteins
  • Nitrophenols
  • Piperazines
  • RNA, Small Interfering
  • Sulfonamides
  • Chloroquine