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Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non–small lung cancer with EGFR TKIs-resistant mutation

  • Feng Pan
  • Jing Tian
  • Xuchao Zhang
  • Ying Zhang
  • Yueyin Pan
Original Paper

Abstract

Purpose

Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non–small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs.

Methods

NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting.

Results

Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest.

Conclusions

Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration.

Keywords

Sunitinib Docetaxel NSCLC Sequence treatment 

Notes

Acknowledgments

This work was granted by Anhui Provincial Science and Technology Agency Foundation of China (No. 07020304102) and supported by Guangdong Lung Cancer institute, Guangdong Academy of Medical Sciences. We thank Dr. Hongxia Tian for FACS analysis.

Conflict of interest

The authors declare no potential conflict of interest.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
  2. 2.Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiChina
  3. 3.Guangdong Lung Cancer Institute, Medical Research Center of Guangdong General HospitalGuangdong Academy of Medical SciencesGuangzhouChina
  4. 4.Department of GeriatricsThe Third Affiliated Hospital of Anhui Medical UniversityHefeiChina

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