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Schedule-dependent synergistic interaction between docetaxel and gefitinib in NSCLC cell lines regardless of the mutation status of EGFR and KRAS and its molecular mechanisms

  • Original Article – Cancer Research
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Abstract

Background

Tyrosine-kinase inhibitors (TKIs) and chemotherapy had different pharmacological mechanisms and therefore combined administration of TKIs and chemotherapy agents may have synergy. Our research aimed at exploring the cytotoxic interactions between gefitinib and docetaxel with different concentrations for non-small-cell lung cancer cell lines, and furthermore, the mechanisms underlying the cytotoxic synergism.

Methods

NCI-H1650 [epidermal growth factor receptor (EGFR) mutation and KRAS wild-type], NCI-H292 (EGFR wild-type and KRAS wild-type) and A549 (EGFR wild-type and KRAS mutation) cell lines were treated with docetaxel and/or gefitinib. Cytotoxic interactions, cell cycle distribution and cell signal pathway were analyzed, respectively.

Results

Cytotoxic interactions between docetaxel and gefitinib were dose-dependent and sequence-dependent in all these three cell lines. Docetaxel followed by gefitinib treatment was optimum regimen regardless of the mutation status of EGFR and KRAS. KRAS mutation and EGFR wild-type predicted insensitive to gefitinib and docetaxel combined treatment as well as gefitinib alone. G1 arrest was inconsistently associated with combination index (CI). However, apoptosis induction was schedule-dependent and can explain the synergism completely. Mitogen-activated protein kinase (MAPK) phosphorylation ratio was also schedule-dependent and positively correlated with CI.

Conclusion

Cytotoxic interactions between docetaxel and gefitinib were sequence-dependent regardless of the mutation status of EGFR and KRAS. Cell characteristic, apoptosis induction and MAPK phosphorylation but not cell cycle change may explain the molecular mechanisms of synergism.

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Acknowledgments

We thank Dr. Li of IMM have provided us cell lines and drug.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Respiratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China

    Yanwen Jiang, Qing Yuan & Qiuhong Fang

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  1. Yanwen Jiang
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  2. Qing Yuan
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  3. Qiuhong Fang
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Correspondence to Qiuhong Fang.

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Jiang, Y., Yuan, Q. & Fang, Q. Schedule-dependent synergistic interaction between docetaxel and gefitinib in NSCLC cell lines regardless of the mutation status of EGFR and KRAS and its molecular mechanisms. J Cancer Res Clin Oncol 140, 1087–1095 (2014). https://doi.org/10.1007/s00432-014-1671-x

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  • DOI: https://doi.org/10.1007/s00432-014-1671-x

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