Advertisement

Investigational New Drugs

, Volume 31, Issue 5, pp 1125–1135 | Cite as

Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA

  • Serena MarchettiEmail author
  • Dick Pluim
  • Monique van Eijndhoven
  • Olaf van Tellingen
  • Roberto Mazzanti
  • Jos H. Beijnen
  • Jan H. M. Schellens
PRECLINICAL STUDIES

Summary

We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for P-glycoprotein (Pgp, MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in vitro. Cell survival, drug transport, and competition experiments with barasertib pro-drug and the more active form of the drug (barasertib-hQPA) were performed using MDCKII (wild type, MDR1, BCRP, and MRP2) and LLCPK (wild type and MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. Moreover we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in vivo using Bcrp1-/-/Mdr1a/1b -/- (triple knockout) and wild type mice. In cell survival experiments expression of BCRP and MDR1 resulted in significant resistance to barasertib. In transwell experiments, barasertib-hQPA was transported by BCRP and MDR1 efficiently. In Sf9-BCRP membrane vesicles, both barasertib and barasertib-hQPA significantly inhibited the BCRP-mediated transport of methotrexate. In contrast, no active transport of barasertib by MRP2 was observed, and overexpression of MRP2 did not affect cytotoxicity of barasertib. In vivo, systemic exposure as well as bioavailability, brain penetration, kidney and liver distribution and myelotoxicity of barasertib-hQPA were statistically significantly increased in Bcrp1-/-/Mdr1a/1b-/- compared with wild type mice (p<0.001). Barasertib is transported efficiently by P-gp and BCRP/Bcrp1 in vitro. In vivo, genetic deletion of P-gp and BCRP in mice significantly affected pharmacokinetics, tissue distribution and myelotoxicity of barasertib-hQPA. Possible clinical consequences for the observed affinity of barasertib for P-gp and BCRP need to be explored.

Keywords

Barasertib AZD1152 Drug efflux transporters BCRP P-glycoprotein MRP2 Aurora kinase 

Notes

Conflict of interest

The authors disclose no potential conflict of interest.

References

  1. 1.
    Wilkinson RW, Odedra R, Heaton SP et al (2007) AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 3:3682–3688CrossRefGoogle Scholar
  2. 2.
    Carmena M, Earnshaw WC (2003) The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4:842–854CrossRefGoogle Scholar
  3. 3.
    Kimura M, Matsuda Y, Yoshioka T et al (1998) Identification and characterization of STK12/Aik2: a human gene related to aurora of Drosophila and yeast IPL1. Cytogenet Cell Genet 82:147–152CrossRefGoogle Scholar
  4. 4.
    Marumoto T, Zhang D, Saya H (2005) Aurora-A - a guardian of poles. Nat Rev Cancer 5:42–50CrossRefGoogle Scholar
  5. 5.
    Tang CJ, Lin CY, Tang TK (2006) Dynamic localization and functional implications of Aurora-C kinase during male mouse meiosis. Dev Biol 290:398–410CrossRefGoogle Scholar
  6. 6.
    Bischoff JR, Anderson L, Zhu Y et al (1998) A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065CrossRefGoogle Scholar
  7. 7.
    Nair JS, de Stanchina E, Schwartz GK (2009) The topoisomerase I poison CPT-11 enhances the effect of the aurora B kinase inhibitor AZD1152 both in vitro and in vivo. Clin Cancer Res 15:2022–2030CrossRefGoogle Scholar
  8. 8.
    Lee EC, Frolov A, Li R et al (2006) Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 66:4996–5002CrossRefGoogle Scholar
  9. 9.
    Chieffi P, Cozzolino L, Kisslinger A et al (2006) Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 66:326–333CrossRefGoogle Scholar
  10. 10.
    Li D, Zhu J, Firozi PF et al (2003) Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 9:991–997PubMedGoogle Scholar
  11. 11.
    Gully CP, Zhang F, Chen J et al (2010) Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol Cancer 9:42CrossRefGoogle Scholar
  12. 12.
    Tanaka T, Kimura M, Matsunaga K et al (1999) Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 59:2041–2044PubMedGoogle Scholar
  13. 13.
    Smith SL, Bowers NL, Betticher DC et al (2005) Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability. Br J Cancer 93:719–729CrossRefGoogle Scholar
  14. 14.
    Sorrentino R, Libertini S, Pallante PL et al (2005) Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 90:928–935CrossRefGoogle Scholar
  15. 15.
    Oke A, Pearce D, Wilkinson RW et al (2009) AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res 69:4150–4158CrossRefGoogle Scholar
  16. 16.
    Moore AS, Blagg J, Linardopoulos S et al (2010) Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 24:671–678CrossRefGoogle Scholar
  17. 17.
    Evans RP, Naber C, Steffler T et al (2008) The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma. Br J Haematol 140:295–302CrossRefGoogle Scholar
  18. 18.
    Ikezoe T, Takeuchi T, Yang J et al (2009) Analysis of Aurora B kinase in non-Hodgkin lymphoma. Lab Invest 89:1364–1373CrossRefGoogle Scholar
  19. 19.
    Reiter R, Gais P, Jütting U et al (2006) Aurora kinase A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma. Clin Cancer Res 12:5136–5141CrossRefGoogle Scholar
  20. 20.
    Lin ZZ, Jeng YM, Hu FC et al (2010) Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC. BMC Cancer 10:461CrossRefGoogle Scholar
  21. 21.
    Boss DS, Witteveen PO, van der Sar J et al (2011) Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann Oncol 22:431–437CrossRefGoogle Scholar
  22. 22.
    Zhu X, Ma Y, Liu D (2010) Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights. J Hematol Oncol 3:17CrossRefGoogle Scholar
  23. 23.
    Marchetti S, Mazzanti R, Beijnen JH et al (2007) Clinical Relevance: drug-drug interaction, pharmacokinetics, pharmacodynamic, and toxicity. Wiley & Sons, Drug Transporters, pp 747–880Google Scholar
  24. 24.
    Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592CrossRefGoogle Scholar
  25. 25.
    Kruitzer CM, Beijnen JH, Sshellens JH (2002) Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview. Oncologist 7:516–530CrossRefGoogle Scholar
  26. 26.
    Breedveld P, Beijnen JH, Schellens JH (2006) Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci 27:17–24CrossRefGoogle Scholar
  27. 27.
    Breedveld P, Pluim D, Cipriani G et al (2005) The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 65:2577–2582CrossRefGoogle Scholar
  28. 28.
    Marchetti S, Mazzanti R, Beijnen JH et al (2007) Concise review: clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 12:927–941CrossRefGoogle Scholar
  29. 29.
    Marchetti S, Oostendorp RL, Pluim D et al (2007) In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2. Mol Cancer Ther 6:3307–3313CrossRefGoogle Scholar
  30. 30.
    de Bruin M, Miyake K, Litman K et al (1999) Reversal of resistance by GF120918 in cell lines expressing the half-transporter, MXR. Cancer Lett 146:117–126CrossRefGoogle Scholar
  31. 31.
    Shepard RL, Cao J, Starling JJ et al (2003) Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. Int J Cancer 103:121–125CrossRefGoogle Scholar
  32. 32.
    Breedveld P, Zelcer N, Pluim D et al (2004) Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res 64:5804–5811CrossRefGoogle Scholar
  33. 33.
    van Herwaarden AE, Jonker JW, Wagenaar E et al (2003) The breast cancer resistance protein (Bcrp1/Abcg2) restricts exposure to the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Cancer Res 63:6447–6452PubMedGoogle Scholar
  34. 34.
    Schinkel AH, Smit JJ, van Tellingen O et al (1994) Disruption of the Mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77:491–502CrossRefGoogle Scholar
  35. 35.
    Pluim D, Beijnen JH, Schellens JH et al (2009) Simultaneous determination of AZD1152 (prodrug) and AZD1152-hydroxyquinazoline pyrazol anilide by reversed phase liquid chromatography. J Chromatogr B Anal Technol Biomed Life Sci 877:3549–3555CrossRefGoogle Scholar
  36. 36.
    Maliepaard M, van Gastelen MA, de Jong LA et al (1999) Overexpression of the BCRP/MXR/ABCP Gene in a Topotecan-selected Ovarian Tumor Cell Line. Cancer Res 59:4559–4563PubMedGoogle Scholar
  37. 37.
    Brangi M, Litman T, Ciotti M et al (1999) Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res 59:4559–4563Google Scholar
  38. 38.
    Schinkel AH, Wagenaar E, van Deemter L et al (1995) Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96:1698–1705CrossRefGoogle Scholar
  39. 39.
    Jonker JW, Smit JW, Brinkhuis RF et al (2000) Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 92:1651–1656CrossRefGoogle Scholar
  40. 40.
    Schinkel AH, Wagenaar E, Mol CA et al (1996) P-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–2524CrossRefGoogle Scholar
  41. 41.
    Kim M, Turnquist H, Jackson J et al (2002) The Multidrug Resistance Transporter ABCG2 (Breast Cancer Resistance Protein 1) Effluxes Hoechst 33342 and Is Overexpressed in Hematopoietic Stem Cells. Clin Canc Res 8:22–28Google Scholar
  42. 42.
    Svirnovski AI, Shman TV, Serhiyenka TF et al (2009) ABCB1 and ABCG2 proteins, their functional activity and gene expression in concert with drug sensitivity of leukemia cells. Hematology 14:204–212CrossRefGoogle Scholar
  43. 43.
    Schinkel AH, Mayer U, Wagenaar E et al (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 94:4028–4033CrossRefGoogle Scholar
  44. 44.
    Ekins S, Ecker GF, Chiba P et al (2007) Future directions for drug transporter modeling. Xenobiotica 37:1152–1170CrossRefGoogle Scholar
  45. 45.
    International Transporter Consortium, Giacomini KM, Huang SM et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236CrossRefGoogle Scholar
  46. 46.
    Kawasaki A, Mastumura I, Miyagawa J (2001) Downregulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells. J Cell Biol 152:275–287CrossRefGoogle Scholar
  47. 47.
    Dennis M, Davies M, Oliver S et al (2012) Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia. Cancer Chemother Pharmacol 70:461–469CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Serena Marchetti
    • 1
    • 4
    Email author
  • Dick Pluim
    • 1
  • Monique van Eijndhoven
    • 1
  • Olaf van Tellingen
    • 1
  • Roberto Mazzanti
    • 3
  • Jos H. Beijnen
    • 2
  • Jan H. M. Schellens
    • 1
    • 2
  1. 1.Department of Experimental Therapy and Medical OncologyThe Netherlands Cancer InstituteAmsterdamthe Netherlands
  2. 2.Science Faculty, Department of Pharmaceutical SciencesUtrecht UniversityUtrechtthe Netherlands
  3. 3.Medical Oncology Unit 2Azienda Ospedaliero-Universitaria Careggi, University of FlorenceFlorenceItaly
  4. 4.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands

Personalised recommendations