Gefitinib enhances cytotoxicities of antimicrotubule agents in non-small-cell lung cancer cells exhibiting no sensitizing epidermal growth factor receptor mutation

Chun Ming Tsai, Chao Hua Chiu, Kao Ting Chang, Jen Ting Chen, Chun Liang Lai, Yuh Min Chen, Shih Yin Hsiao

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

INTRODUCTIONS:: Although randomized clinical trials showed no benefit from combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with standard chemotherapy for advanced non-small-cell lung cancer (NSCLC), better results might be obtained by combining EGFR-TKI with individual agents that are substrates for the adenosine triphosphate binding cassette transporters (ABCTs) because EGFR-TKIs can inhibit their efflux. The combination effects deserved to be further examined in vitro. METHODS:: The combination effects of gefitinib with three antimicrotubule agents (AMTAs), paclitaxel, docetaxel or vinorelbine, or with gemcitabine were tested in 17 NSCLC cell lines using the tetrazolium colorimetric assay and classical isobole method. The effects of drug combinations, identified by the values of mean combination index (mCIs), were correlated with the expression levels of ABCTs. Dose-versus-log-response curves were analyzed to further evaluate the possible mechanisms of drug interactions. RESULTS:: Synergistic gefitinib/AMTA interactions were observed in the tested cell lines. The synergism was more robust in the four lines overexpressing de novo or acquired P-glycoprotein (Pgp; individual mCIs range, 0.484-0.859; all p values were < 0.05), or in 12 cell lines exhibiting no sensitizing EGFR mutations (group mCIs for gefitinib/paclitaxel, gefitinib/docetaxel, and gefitinib/vinorelbine were 0.869, 0.82, and 0.853, respectively. All p values were < 0.02). The synergism could be observed in cells expressing nearly undetectable Pgp and other ABCTs tested in this study. The combination of gefitinib/gemcitabine was additive (mCI = 1.027). CONCLUSIONS:: Combined gefitinib/AMTAs showed synergism in NSCLC cells harboring no sensitizing EGFR mutations. Gefitinib could enhance AMTA effects through mechanisms not restricted to Pgp blockage.

Original languageEnglish (US)
Pages (from-to)1218-1227
Number of pages10
JournalJournal of Thoracic Oncology
Volume7
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Antimicrotubule agent
  • Gefitinib
  • Nonsmall-cell lung cancer
  • P-glycoprotein
  • Synergism

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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