Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line

Front Med. 2013 Dec;7(4):462-76. doi: 10.1007/s11684-013-0270-6. Epub 2013 Jul 2.

Abstract

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

Publication types

  • Evaluation Study

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects*
  • Benzodiazepinones / administration & dosage
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Female
  • Gemcitabine
  • Humans
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oligonucleotide Array Sequence Analysis
  • Pyrazoles / administration & dosage
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spheroids, Cellular / drug effects*
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzodiazepinones
  • Biomarkers, Tumor
  • PF 00477736
  • Pyrazoles
  • Deoxycytidine
  • Gemcitabine