Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Dean M, Rzhetsky A, Allikmets R (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 11:1156–1166

    Article  PubMed  CAS  Google Scholar 

  2. Gillet JP, Efferth T, Remacle J (2007) Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochim Biophys Acta 1775:237–262

    PubMed  CAS  Google Scholar 

  3. Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162

    Article  PubMed  CAS  Google Scholar 

  4. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE et al (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485

    Article  PubMed  CAS  Google Scholar 

  5. Cole SP, Bhardwaj G, Gerlach JH et al (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654

    Article  PubMed  CAS  Google Scholar 

  6. Loe DW, Deeley RG, Cole SP (1998) Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res 58:5130–5136

    PubMed  CAS  Google Scholar 

  7. Hegedus T, Orfi L, Seprodi A et al (2002) Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta 1587:318–325

    PubMed  CAS  Google Scholar 

  8. Kitazaki T, Oka M, Nakamura Y et al (2005) Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 49:337–343

    Article  PubMed  Google Scholar 

  9. Houghton PJ, Germain GS, Harwood FC et al (2004) Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 64:2333–2337

    Article  PubMed  CAS  Google Scholar 

  10. Shi Z, Peng XX, Kim IW et al (2007) Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res 67:11012–11020

    Article  PubMed  CAS  Google Scholar 

  11. Dai CL, Tiwari AK, Wu CP et al (2008) Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res 68:7905–7914

    Article  PubMed  CAS  Google Scholar 

  12. Mi Y, Lou L (2007) ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein. Br J Cancer 97:934–940

    Article  PubMed  CAS  Google Scholar 

  13. Wedge SR, Kendrew J, Hennequin LF et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  PubMed  CAS  Google Scholar 

  14. Zhang JY, Wu HY, Xia XK et al (2007) Anthracenedione derivative 1403P-3 induces apoptosis in KB and KBv200 cells via reactive oxygen species-independent mitochondrial pathway and death receptor pathway. Cancer Biol Ther 6:1413–1421

    Article  PubMed  CAS  Google Scholar 

  15. Fu L, Liang Y, Deng L et al (2004) Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Chemother Pharmacol 53:349–356

    Article  PubMed  CAS  Google Scholar 

  16. Sumizawa T, Chuman Y, Sakamoto H et al (1994) Non-P-glycoprotein-mediated multidrug-resistant human KB cells selected in medium containing adriamycin, cepharanthine, and mezerein. Somat Cell Mol Genet 20:423–435

    Article  PubMed  CAS  Google Scholar 

  17. Chen LM, Wu XP, Ruan JW et al (2004) Screening novel, potent multidrug-resistant modulators from imidazole derivatives. Oncol Res 14:355–362

    PubMed  CAS  Google Scholar 

  18. Sumizawa T, Chen ZS, Chuman Y et al (1997) Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P. Mol Pharmacol 51:399–405

    PubMed  CAS  Google Scholar 

  19. West KA, Castillo SS, Dennis PA (2002) Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat 5:234–248

    Article  PubMed  CAS  Google Scholar 

  20. McCubrey JA, Steelman LS, Chappell WH et al (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773:1263–1284

    Article  PubMed  CAS  Google Scholar 

  21. Nikolinakos P, Heymach JV (2008) The tyrosine kinase inhibitor cediranib for non-small cell lung cancer and other thoracic malignancies. J Thorac Oncol 3:S131–S134

    PubMed  Google Scholar 

  22. Laurie SA, Gauthier I, Arnold A et al (2008) Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. J Clin Oncol 26:1871–1878

    Article  PubMed  CAS  Google Scholar 

  23. Gomez-Rivera F, Santillan-Gomez AA, Younes MN et al (2007) The tyrosine kinase inhibitor, AZD2171, inhibits vascular endothelial growth factor receptor signaling and growth of anaplastic thyroid cancer in an orthotopic nude mouse model. Clin Cancer Res 13:4519–4527

    Article  PubMed  CAS  Google Scholar 

  24. Drevs J, Siegert P, Medinger M et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054

    Article  PubMed  CAS  Google Scholar 

  25. Takeda M, Arao T, Yokote H et al (2007) AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res 13:3051–3057

    Article  PubMed  CAS  Google Scholar 

  26. Shukla S, Sauna ZE, Ambudkar SV (2008) Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia 22:445–447

    Article  PubMed  CAS  Google Scholar 

  27. Brendel C, Scharenberg C, Dohse M et al (2007) Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 21:1267–1275

    Article  PubMed  CAS  Google Scholar 

  28. Coley HM, Shotton CF, Ajose-Adeogun A et al (2006) Receptor tyrosine kinase (RTK) inhibition is effective in chemosensitising EGFR-expressing drug resistant human ovarian cancer cell lines when used in combination with cytotoxic agents. Biochem Pharmacol 72:941–948

    Article  PubMed  CAS  Google Scholar 

  29. Normanno N, De Luca A, Bianco C et al (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16

    Article  PubMed  CAS  Google Scholar 

  30. Grant S, Qiao L, Dent P (2002) Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front Biosci 7:d376–d389

    Article  PubMed  CAS  Google Scholar 

  31. Knuefermann C, Lu Y, Liu B et al (2003) HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22:3205–3212

    Article  PubMed  CAS  Google Scholar 

  32. Li QQ, Wang WJ, Xu JD et al (2007) Involvement of CD147 in regulation of multidrug resistance to P-gp substrate drugs and in vitro invasion in breast cancer cells. Cancer Sci 98:1064–1069

    Article  PubMed  CAS  Google Scholar 

  33. Colone M, Calcabrini A, Toccacieli L et al (2008) The multidrug transporter P-glycoprotein: a mediator of melanoma invasion? J Invest Dermatol 128:957–971

    Article  PubMed  CAS  Google Scholar 

  34. Osborn MT, Berry A, Ruberu MS et al (1999) Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways. Oncogene 18:5756–5764

    Article  PubMed  CAS  Google Scholar 

  35. Ambudkar SV, Dey S, Hrycyna CA et al (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, 651 Dongfeng East Road, 510060, Guangzhou, China

    Li-yang Tao, Yong-ju Liang, Fang Wang, Li-ming Chen, Yan-yan Yan, Chun-ling Dai & Li-wu Fu

Authors
  1. Li-yang Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong-ju Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li-ming Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan-yan Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chun-ling Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li-wu Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li-wu Fu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tao, Ly., Liang, Yj., Wang, F. et al. Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother Pharmacol 64, 961–969 (2009). https://doi.org/10.1007/s00280-009-0949-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-009-0949-1

Keywords

Search

Navigation