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Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 5, pp 961–969 | Cite as

Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function

  • Li-yang Tao
  • Yong-ju Liang
  • Fang Wang
  • Li-ming Chen
  • Yan-yan Yan
  • Chun-ling Dai
  • Li-wu Fu
Original Article

Abstract

Purpose

Cediranib (recentin, AZD2171) is an oral small-molecule multiple receptor tyrosine kinases inhibitor. Here we investigate the ability of cediranib to reverse tumor multidrug resistance (MDR) due to overexpression of ABCB1 (P-glycoprotein) and ABCC1 (MRP1) transporters.

Methods

KBv200,MCF-7/adr, C-A120 and their parental sensitive cell lines KB, MCF-7 and KB-3-1 were used for reversal study. The intracellular accumulations of doxorubicin and rhodamine 123 were determined by flow cytometry. The expressions levels of ABCB1 and ABCC1 were investigated by Western blot and RT-PCR analyses. ATPase activity assay were performed by Luminescence. The functions of ERK in MCF-7/adr were investigated by RNA interference.

Results

Cediranib significantly enhanced the sensitivity of ABCB1 or ABCC1 substrates in MDR cells, with no effect found on sensitive cells. However, the expressions of these transporters were not affected and the reversal activity of cediranib was not related to the phosphorylation of AKT or ERK1/2. Further studies showed that cediranib inhibited ATPase activity of ABCB1 (P-glycoprotein) in a dose-dependent manner.

Conclusions

Cediranib reverses ABCB1- and ABCC1-mediated MDR by directly inhibiting their drug efflux function. These findings may be useful for cancer combinational therapy with cediranib in the clinic.

Keywords

Multidrug resistance Cediranib ATP-binding cassette transporters Tyrosine kinases inhibitor 

Notes

Acknowledgments

We thank professor Xu-yi Liu (Cancer Hospital of Beijing, China) for ABCB1 overexpressing KBv200 cells and parental sensitive KB cells. The work was supported by grants from China National Natural Sciences Foundation No. 30672407,No. 30600769, Medical Science and Technology Research Foundation of Guang Dong Province No. A2006224 and 863 Project Foundation No. 2006AA09Z419.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Li-yang Tao
    • 1
  • Yong-ju Liang
    • 1
  • Fang Wang
    • 1
  • Li-ming Chen
    • 1
  • Yan-yan Yan
    • 1
  • Chun-ling Dai
    • 1
  • Li-wu Fu
    • 1
  1. 1.State Key Laboratory of Oncology in South China, Cancer CenterSun Yat-Sen UniversityGuangzhouChina

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