Cellular Oncology

, Volume 34, Issue 1, pp 33–44 | Cite as

Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance

  • Qing-feng Xiang
  • Fang Wang
  • Xiao-dong Su
  • Yong-ju Liang
  • Li-sheng Zheng
  • Yan-jun Mi
  • Wei-qiang Chen
  • Li-wu Fu
Original Paper



The overexpression of ATP-binding cassette (ABC) transporters is one of the main causes of multi-drug resistance (MDR) which represents a major obstacle to the success of cancer chemotherapy. In this study, we examined the effect of BIBF 1120, an inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs) tyrosine kinases, on the reversal of multidrug resistance in vitro.


The doxorubicin and rhodamine 123 retention assay was performed by flowcytometry. Western blot were employed to identify ABCB1 expression level and the effect of BIBF 1120 on the blockade of Akt and ERK1/2 phosphorylation. The expression of mdr1 mRNA was determined by RT-PCR analysis. The ATPase activity of ABCB1 was investigated using Pgp-Glo™ assay systems.


BIBF 1120 significantly enhanced the cytotoxicity of doxorubicin and paclitaxel and increased the accumulation of ABCB1 substrates in ABCB1-overexpressing cancer cells, whereas it had no effect on the parental cells. On the other hand, BIBF 1120 did not alter the cytotoxicity of non-ABCB1 substrates and was unable to reverse ABCC1 or ABCG2-mediated MDR. Furthermore, BIBF 1120 inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. However, no detectable alteration on the expression level of mdr1 mRNA or ABCB1 protein was identified in ABCB1-overexpressing cancer cells by different treatments of BIBF 1120. Interestly, total and phosphorylated forms of AKT and ERK1/2 were not inhibited by BIBF 1120 at the reversal concentrations.


Our results suggest that BIBF 1120 is capable of overcoming ABCB1-mediated drug resistance by inhibiting ABCB1 function, which may have clinical significance for BIBF 1120 combinational treatment of certain resistant cancers.


BIBF 1120 Multidrug resistance ATP-binding cassette transporters ABCB1/P-glycoprotein 



We thank Drs S.E. Bates and R.W. Robey (National Cancer Institute, NIH) for the ABCG2 expressing cell line S1-M1-80 and their parental sensitive cell line S1. The work was supported by grants from China National Natural Sciences Foundation No. 81072669 and No. 81061160.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.


  1. 1.
    M.M. Gottesman, T. Fojo, S.E. Bates, Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48–58 (2002)PubMedCrossRefGoogle Scholar
  2. 2.
    R. Perez-Tomas, Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr. Med. Chem. 13, 1859–1876 (2006)PubMedCrossRefGoogle Scholar
  3. 3.
    M. Dean, A. Rzhetsky, R. Allikmets, The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 11, 1156–1166 (2001)PubMedCrossRefGoogle Scholar
  4. 4.
    C.H. Choi, ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5, 30 (2005)PubMedCrossRefGoogle Scholar
  5. 5.
    U.A. Germann, P-glycoprotein–a mediator of multidrug resistance in tumour cells. Eur. J. Cancer 32A, 927–944 (1996)PubMedCrossRefGoogle Scholar
  6. 6.
    G.D. Leonard, T. Fojo, S.E. Bates, The role of ABC transporters in clinical practice. Oncologist 8, 411–424 (2003)PubMedCrossRefGoogle Scholar
  7. 7.
    D.R. Hipfner, R.G. Deeley, S.P. Cole, Structural, mechanistic and clinical aspects of MRP1. Biochim. Biophys. Acta 1461, 359–376 (1999)PubMedCrossRefGoogle Scholar
  8. 8.
    G. Szakacs, J.P. Annereau, S. Lababidi, U. Shankavaram, A. Arciello, K.J. Bussey, W. Reinhold, Y. Guo, G.D. Kruh, M. Reimers, J.N. Weinstein, M.M. Gottesman, Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 6, 129–137 (2004)PubMedCrossRefGoogle Scholar
  9. 9.
    G. Szakacs, J.K. Paterson, J.A. Ludwig, C. Booth-Genthe, M.M. Gottesman, Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5, 219–234 (2006)PubMedCrossRefGoogle Scholar
  10. 10.
    L.A. Doyle, D.D. Ross, Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22, 7340–7358 (2003)PubMedCrossRefGoogle Scholar
  11. 11.
    L.A. Doyle, W. Yang, L.V. Abruzzo, T. Krogmann, Y. Gao, A.K. Rishi, D.D. Ross, A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl Acad. Sci. USA 95, 15665–15670 (1998)PubMedCrossRefGoogle Scholar
  12. 12.
    N. Haraguchi, T. Utsunomiya, H. Inoue, F. Tanaka, K. Mimori, G.F. Barnard, M. Mori, Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24, 506–513 (2006)PubMedCrossRefGoogle Scholar
  13. 13.
    H.M. Coley, Overcoming multidrug resistance in cancer: clinical studies of p-glycoprotein inhibitors. Meth. Mol. Biol. 596, 341–358 (2010)CrossRefGoogle Scholar
  14. 14.
    M. Dean, T. Fojo, S. Bates, Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005)PubMedCrossRefGoogle Scholar
  15. 15.
    F. Hilberg, G.J. Roth, M. Krssak, S. Kautschitsch, W. Sommergruber, U. Tontsch-Grunt, P. Garin-Chesa, G. Bader, A. Zoephel, J. Quant, A. Heckel, W.J. Rettig, BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008)PubMedCrossRefGoogle Scholar
  16. 16.
    M. Reck, BIBF 1120 for the treatment of non-small cell lung cancer. Expert Opin. Investig. Drugs 19, 789–794 (2010)PubMedCrossRefGoogle Scholar
  17. 17.
    C.L. Dai, A.K. Tiwari, C.P. Wu, X.D. Su, S.R. Wang, D.G. Liu, C.R. Ashby Jr., Y. Huang, R.W. Robey, Y.J. Liang, L.M. Chen, C.J. Shi, S.V. Ambudkar, Z.S. Chen, L.W. Fu, 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 (2008)PubMedCrossRefGoogle Scholar
  18. 18.
    T. Kitazaki, M. Oka, Y. Nakamura, J. Tsurutani, S. Doi, M. Yasunaga, M. Takemura, H. Yabuuchi, H. Soda, S. Kohno, Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 49, 337–343 (2005)PubMedCrossRefGoogle Scholar
  19. 19.
    Z. Shi, X.X. Peng, I.W. Kim, S. Shukla, Q.S. Si, R.W. Robey, S.E. Bates, T. Shen, C.R. Ashby Jr., L.W. Fu, S.V. Ambudkar, Z.S. Chen, 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 (2007)PubMedCrossRefGoogle Scholar
  20. 20.
    L.Y. Tao, Y.J. Liang, F. Wang, L.M. Chen, Y.Y. Yan, C.L. Dai, L.W. Fu, Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother. Pharmacol. 64, 961–969 (2009)PubMedCrossRefGoogle Scholar
  21. 21.
    L.S. Zheng, F. Wang, Y.H. Li, X. Zhang, L.M. Chen, Y.J. Liang, C.L. Dai, Y.Y. Yan, L.Y. Tao, Y.J. Mi, A.K. Yang, K.K. To, L.W. Fu, Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS ONE 4, e5172 (2009)PubMedCrossRefGoogle Scholar
  22. 22.
    C.L. Dai, Y.J. Liang, Y.S. Wang, A.K. Tiwari, Y.Y. Yan, F. Wang, Z.S. Chen, X.Z. Tong, L.W. Fu, Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 279, 74–83 (2009)PubMedCrossRefGoogle Scholar
  23. 23.
    F. Hilberg, I. Brandstetter, Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapy: C7-03, Journal of Thoracic Oncology 2 (2007) S380 310.1097/1001.JTO.0000283231.0000276336.0000283201.Google Scholar
  24. 24.
    A. du Bois, J. Huober, P. Stopfer, J. Pfisterer, P. Wimberger, S. Loibl, V.L. Reichardt, P. Harter, A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann. Oncol. 21, 370–375 (2010)PubMedCrossRefGoogle Scholar
  25. 25.
    M. Reck, R. Kaiser, C. Eschbach, M. Stefanic, J. Love, U. Gatzemeier, J. von Pawel, Phase II double blind study to investigate efficacy and safety of the triple angiokinase inhibitor BIBF 1120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC): B1-03, Journal of Thoracic Oncology 2 (2007) S333-S334 310.1097/1001.JTO.0000283141.0000268423.c0000283145.Google Scholar
  26. 26.
    L. Fu, Y. Liang, L. Deng, Y. Ding, L. Chen, Y. Ye, X. Yang, Q. Pan, Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Chemother. Pharmacol. 53, 349–356 (2004)PubMedCrossRefGoogle Scholar
  27. 27.
    R.W. Robey, Y. Honjo, K. Morisaki, T.A. Nadjem, S. Runge, M. Risbood, M.S. Poruchynsky, S.E. Bates, Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br. J. Cancer 89, 1971–1978 (2003)PubMedCrossRefGoogle Scholar
  28. 28.
    P.M. Tang, D.M. Zhang, N.H. Xuan, S.K. Tsui, M.M. Waye, S.K. Kong, W.P. Fong, K.P. Fung, Photodynamic therapy inhibits P-glycoprotein mediated multidrug resistance via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a. Mol. Cancer 8, 56 (2009)PubMedCrossRefGoogle Scholar
  29. 29.
    R. Tang, A.M. Faussat, P. Majdak, J.Y. Perrot, D. Chaoui, O. Legrand, J.P. Marie, Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. Leukemia 18, 1246–1251 (2004)PubMedCrossRefGoogle Scholar
  30. 30.
    L.M. Chen, X.P. Wu, J.W. Ruan, Y.J. Liang, Y. Ding, Z. Shi, X.W. Wang, L.Q. Gu, L.W. Fu, Screening novel, potent multidrug-resistant modulators from imidazole derivatives. Oncol. Res. 14, 355–362 (2004)PubMedGoogle Scholar
  31. 31.
    Z. Shi, Y.J. Liang, Z.S. Chen, X.W. Wang, X.H. Wang, Y. Ding, L.M. Chen, X.P. Yang, L.W. Fu, Reversal of MDR1/P-glycoprotein-mediated multidrug resistance by vector-based RNA interference in vitro and in vivo. Cancer Biol. Ther. 5, 39–47 (2006)PubMedGoogle Scholar
  32. 32.
    J.M. Ford, W.N. Hait, Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol. Rev. 42, 155–199 (1990)PubMedGoogle Scholar
  33. 33.
    L.M. Chen, Y.J. Liang, J.W. Ruan, Y. Ding, X.W. Wang, Z. Shi, L.Q. Gu, X.P. Yang, L.W. Fu, Reversal of P-gp mediated multidrug resistance in-vitro and in-vivo by FG020318. J. Pharm. Pharmacol. 56, 1061–1066 (2004)PubMedCrossRefGoogle Scholar
  34. 34.
    H. Minderman, K.L. O’Loughlin, L. Pendyala, M.R. Baer, VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin. Cancer Res. 10, 1826–1834 (2004)PubMedCrossRefGoogle Scholar
  35. 35.
    P. Limtrakul, O. Khantamat, K. Pintha, Inhibition of P-glycoprotein activity and reversal of cancer multidrug resistance by Momordica charantia extract. Cancer Chemother. Pharmacol. 54, 525–530 (2004)PubMedCrossRefGoogle Scholar
  36. 36.
    V. Gagnon, C. Van Themsche, S. Turner, V. Leblanc, E. Asselin, Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol. Apoptosis 13, 259–271 (2008)PubMedCrossRefGoogle Scholar
  37. 37.
    S.Y. Oh, J.H. Song, J.E. Gil, J.H. Kim, Y.I. Yeom, E.Y. Moon, ERK activation by thymosin-beta-4 (TB4) overexpression induces paclitaxel-resistance. Exp. Cell Res. 312, 1651–1657 (2006)PubMedCrossRefGoogle Scholar
  38. 38.
    R.S. Herbst, Therapeutic options to target angiogenesis in human malignancies. Expert Opin. Emerg. Drugs 11, 635–650 (2006)PubMedCrossRefGoogle Scholar
  39. 39.
    A. Morabito, E. De Maio, M. Di Maio, N. Normanno, F. Perrone, Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 11, 753–764 (2006)PubMedCrossRefGoogle Scholar
  40. 40.
    L. Zahiragic, C. Schliemann, R. Bieker, N.H. Thoennissen, K. Burow, C. Kramer, M. Zuhlsdorf, W.E. Berdel, R.M. Mesters, Bevacizumab reduces VEGF expression in patients with relapsed and refractory acute myeloid leukemia without clinical antileukemic activity. Leukemia 21, 1310–1312 (2007)PubMedCrossRefGoogle Scholar
  41. 41.
    F.J. Giles, W.T. Bellamy, Z. Estrov, S.M. O’Brien, S. Verstovsek, F. Ravandi, M. Beran, P. Bycott, Y. Pithavala, H. Steinfeldt, S.D. Reich, A.F. List, K.W. Yee, The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk. Res. 30, 801–811 (2006)PubMedCrossRefGoogle Scholar
  42. 42.
    O. Casanovas, D.J. Hicklin, G. Bergers, D. Hanahan, Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299–309 (2005)PubMedCrossRefGoogle Scholar
  43. 43.
    S.A. Antoniu, M.R. Kolb, Intedanib, a triple kinase inhibitor of VEGFR, FGFR and PDGFR for the treatment of cancer and idiopathic pulmonary fibrosis. IDrugs 13, 332–345 (2010)PubMedGoogle Scholar
  44. 44.
    P.M. Ellis, R. Kaiser, Y. Zhao, P. Stopfer, S. Gyorffy, N. Hanna, Phase I open-label study of continuous treatment with BIBF 1120, a triple angiokinase inhibitor, and pemetrexed in pretreated non-small cell lung cancer patients. Clin. Cancer Res. 16, 2881–2889 (2010)PubMedCrossRefGoogle Scholar
  45. 45.
    J. Von Pawel, R. Kaiser, C. Eschbach, M. Stefanic, J. Love, U. Gatzemeier, M. Reck, A double blind phase II study of BIBF 1120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC), J Clin Oncol (Meeting Abstracts) 25, 7635 (2007)Google Scholar
  46. 46.
    G.A. Fisher, B.L. Lum, J. Hausdorff, B.I. Sikic, Pharmacological considerations in the modulation of multidrug resistance. Eur. J. Cancer 32A, 1082–1088 (1996)PubMedCrossRefGoogle Scholar
  47. 47.
    Y.P. Hu, P. Pourquier, F. Doignon, M. Crouzet, J. Robert, Effects of modulators of multidrug resistance on the expression of the MDR1 gene on human KB cells in culture. Anticancer Drugs 7, 738–744 (1996)PubMedCrossRefGoogle Scholar
  48. 48.
    K.A. West, S.S. Castillo, P.A. Dennis, Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist. Updat. 5, 234–248 (2002)PubMedCrossRefGoogle Scholar
  49. 49.
    J.A. McCubrey, L.S. Steelman, W.H. Chappell, S.L. Abrams, E.W. Wong, F. Chang, B. Lehmann, D.M. Terrian, M. Milella, A. Tafuri, F. Stivala, M. Libra, J. Basecke, C. Evangelisti, A.M. Martelli, R.A. Franklin, Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 1773, 1263–1284 (2007)PubMedCrossRefGoogle Scholar
  50. 50.
    C. Knuefermann, Y. Lu, B. Liu, W. Jin, K. Liang, L. Wu, M. Schmidt, G.B. Mills, J. Mendelsohn, Z. Fan, HER2/PI-3 K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22, 3205–3212 (2003)PubMedCrossRefGoogle Scholar
  51. 51.
    R. Krishna, L.D. Mayer, Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur. J. Pharm. Sci. 11, 265–283 (2000)PubMedCrossRefGoogle Scholar
  52. 52.
    S.V. Ambudkar, S. Dey, C.A. Hrycyna, M. Ramachandra, I. Pastan, M.M. Gottesman, Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39, 361–398 (1999)PubMedCrossRefGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2011

Authors and Affiliations

  • Qing-feng Xiang
    • 1
    • 2
  • Fang Wang
    • 2
  • Xiao-dong Su
    • 2
  • Yong-ju Liang
    • 2
  • Li-sheng Zheng
    • 2
  • Yan-jun Mi
    • 2
  • Wei-qiang Chen
    • 1
  • Li-wu Fu
    • 2
  1. 1.Department of General Surgery, Chen Xing Hai HospitalGuangdong Medical CollegeZhongshanChina
  2. 2.State Key Laboratory of Oncology in Southern China, Cancer CenterSun Yat-Sen UniversityGuangzhouChina

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