Schedule-dependent interaction between the proteosome inhibitor bortezomib and the EGFR-TK inhibitor erlotinib in human non-small cell lung cancer cell lines

J Thorac Oncol. 2007 Aug;2(8):715-21. doi: 10.1097/JTO.0b013e3180f60bb3.

Abstract

Introduction: Both erlotinib (E) and bortezomib (B) have shown single-agent activity in patients with non-small cell lung cancer. We studied the combination of these two novel biologic agents in vitro using a panel of non-small cell lung cancer cell lines.

Methods: The growth inhibitory effect of E and B were determined by MTT assay on seven non-small cell lung cancer cell lines. The data obtained from the growth inhibition assay in response to the combination of E and B were subject to isobologram analysis. The effects of each individual drug as well as combination in different sequences on cell cycle and apoptosis were determined by flow cytometry.

Results: Two of seven cell lines are sensitive to E. However, B has narrower range of cytotoxicity. The combination is neither synergistic nor additive in two of four cell lines tested. In H358 bronchoalveolar cell lines, the combination is more active than either agent alone. E causes G1 cell cycle arrest and B causes G2/M cell cycle arrest. In sequential studies, 24-hour previous exposure to E causes G1 arrest and abrogates the cytotoxic effect of B. This is observed in both E-sensitive as well as E-resistant cells and is accompanied by an increase in cell survival and a decrease in apoptosis.

Conclusions: The combination of E and B is neither additive nor synergistic in two of four cell lines tested. In H358 bronchoalveolar cell, the combination is more active than either agent alone. The schedule-dependent antagonistic effect of E pre-exposure was observed. E pre-exposure causes G1 cell cycle arrest and abrogates the activity of B. Further in vivo studies of this combination are warranted.

MeSH terms

  • Apoptosis
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle
  • Cell Proliferation
  • Drug Interactions
  • Drug Therapy, Combination
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Protease Inhibitors / therapeutic use*
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazines / therapeutic use*
  • Quinazolines / therapeutic use*
  • Tumor Cells, Cultured

Substances

  • Boronic Acids
  • Protease Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines
  • Quinazolines
  • Bortezomib
  • Erlotinib Hydrochloride
  • ErbB Receptors