Vemurafenib (PLX4032, Zelboraf®), a BRAF Inhibitor, Modulates ABCB1-, ABCG2-, and ABCC10-Mediated Multidrug Resistance

Authors

  • Saurabh G. Vispute Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Jun-Jiang Chen Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Yue-Li Sun Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Kamlesh S. Sodani Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Satyakam Singh Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Yihang Pan Cytogenetics Laboratory, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA
  • Tanaji Talele Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Charles R. Ashby Jr Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
  • Zhe-Sheng Chen Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA

DOI:

https://doi.org/10.6000/1929-2279.2013.02.04.9

Keywords:

Vemurafenib, ABCC10, ABCG2, MDR.

Abstract

 In this study, we examined the in vitro effects of vemurafenib, a specific inhibitor of V600E mutated BRAFenzyme, on the response of cells overexpressing the ATP binding cassette (ABC) efflux transporters ABCG2, ABCB1, ABCC1 and ABCC10. Vemurafenib, at 5 µM and 20 µM, produced a significant concentration-dependent increase in the cytotoxicity of paclitaxel in cells overexpressing ABCB1 and ABCC10 and mitoxantrone in cells overexpressing ABCG2. Vemurafenib also significantly enhanced the accumulation of paclitaxel in cell lines overexpressing ABCB1 and ABCC10. Vemurafenib significantly increased the intracellular accumulation of mitoxantrone in cells overexpressing ABCG2. In contrast, vemurafenib did not significantly alter the sensitivity of ABCC1 overexpressing HEK/ABCC1 cells to vincristine. Finally, as determined by Western blotting, vemurafenib (20 µM) did not significantly alter the expression of the proteins for ABCG2, ABCC10 or ABCB1. Thus, vemurafenib most likely reverses multidrug resistance by altering the transport function of these aforementioned ABC transporters, as opposed to affecting the expression of ABC proteins. The docking analysis of vemurafenib with the ABCB1 homology model also suggested that vemurafenib binds to the ABCB1 and ABCG2 drug binding site. These findings suggest that combination of specific inhibitors like vemurafenib with chemotherapeutic drugs may be used to overcome multidrug resistance in cells that overexpress ABCB1, ABCC10 and/or ABCG2 transporters.

References

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: A Cancer J Clin 2013; 63(1): 11-30. http://dx.doi.org/10.3322/caac.21166

Shi H, Moriceau G, Kong X, Lee M, Lee H, Koya RC, et al. Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 2012; 3: 724. http://dx.doi.org/10.1038/ncomms1727

Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367(2): 107-14. http://dx.doi.org/10.1056/NEJMoa1203421

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Engl J Med 2011 06/30; 2013/04; 364(26): 2507-16.

Luke JJ, Hodi FS. Vemurafenib and BRAF inhibition: a new class of treatment for metastatic melanoma. Clin Cancer Res 2012; 18(1): 9-14. http://dx.doi.org/10.1158/1078-0432.CCR-11-2197

Mullard A. 2011 FDA drug approvals. Nat Rev Drug Discov 2012; 11(2): 91-94. http://dx.doi.org/10.1038/nrd3657

Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 2012/11; 11(11): 873-86.

Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong X, et al. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 2012; 287(33): 28087-98. http://dx.doi.org/10.1074/jbc.M112.377218

Roukos DH. PLX4032 and melanoma: resistance, expectations and uncertainty. Expert review of anticancer therapy JID - 101123358 0711.

Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP–dependent transporters. Nat Rev Cancer 2002; 2(1): 48-58. http://dx.doi.org/10.1038/nrc706

Shukla S, Wu C, Ambudkar SV. Development of inhibitors of ATP-binding cassette drug transporters-present status and challenges 2008.

Chen KG, Valencia JC, Gillet J, Hearing VJ, Gottesman MM. Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma. Pigment Cell Melanoma Res 2009; 22(6): 740-49. http://dx.doi.org/10.1111/j.1755-148X.2009.00630.x

Choi C. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 2005; 5(1): 30. http://dx.doi.org/10.1186/1475-2867-5-30

Hardwick L, Velamakanni S, Veen H. The emerging pharmacotherapeutic significance of the breast cancer resistance protein (ABCG2). Br J Pharmacol 2007; 151(2): 163-74. http://dx.doi.org/10.1038/sj.bjp.0707218

Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5(3): 219-34. http://dx.doi.org/10.1038/nrd1984

Wu C, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol 2008; 1(2): 93.

Kruh GD, Guo Y, Hopper-Borge E, Belinsky MG, Chen Z. Abcc10, abcc11, and abcc12. Pflügers Archiv-European J Physiol 2007; 453(5): 675-84. http://dx.doi.org/10.1007/s00424-006-0114-1

Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter 1. Annu Rev Pharmacol Toxicol 1999; 39(1): 361-98. http://dx.doi.org/10.1146/annurev.pharmtox.39.1.361

Robey RW, Medina-Pérez WY, Nishiyama K, Lahusen T, Miyake K, Litman T, et al. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res 2001; 7(1): 145-52.

Allen JD, Brinkhuis RF, Wijnholds J, Schinkel AH. The Mouse Bcrp1/Mxr/Abcp Gene Amplification and Overexpression in Cell Lines Selected for Resistance to Topotecan, Mitoxantrone, or Doxorubicin. Cancer Res 1999; 59(17): 4237-41.

Hegedűs T, Őrfi L, Seprődi A, Váradi A, Sarkadi B, Kéri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta (BBA)-Mol Basis Dis 2002; 1587(2): 318-25. http://dx.doi.org/10.1016/S0925-4439(02)00095-9

Dai C, Tiwari AK, Wu C, Su X, Wang S, Liu D, et al. 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 2008; 68(19): 7905-14. http://dx.doi.org/10.1158/0008-5472.CAN-08-0499

Tiwari AK, Sodani K, Dai C, Abuznait AH, Singh S, Xiao Z,

et al. Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft models. Cancer Lett 2013 1/28; 328(2): 307-17.

Shen T, Kuang Y, Ashby CR, Lei Y, Chen A, Zhou Y, et al. Imatinib and nilotinib reverse multidrug resistance in cancer cells by inhibiting the efflux activity of the MRP7 (ABCC10). PLoS One 2009; 4(10): e7520. http://dx.doi.org/10.1371/journal.pone.0007520

Kuang Y, Shen T, Chen X, Sodani K, Hopper-Borge E, Tiwari AK, et al. Lapatinib and erlotinib are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance. Biochem Pharmacol 2010; 79(2): 154-61. http://dx.doi.org/10.1016/j.bcp.2009.08.021

Shi Z, Peng X, Kim I, Shukla S, Si Q, Robey RW, et al. 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 2007; 67(22): 11012-20. http://dx.doi.org/10.1158/0008-5472.CAN-07-2686

Shukla S, Robey RW, Bates SE, Ambudkar SV. Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Disposition 2009; 37(2): 359-65. http://dx.doi.org/10.1124/dmd.108.024612

Hoffmann K, Franz C, Xiao Z, Mohr E, Serba S, Buechler MW, et al. Sorafenib modulates the gene expression of multi-drug resistance mediating ATP-binding cassette proteins in experimental hepatocellular carcinoma. Anticancer Res 2010; 30(11): 4503-508.

Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, et al. Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res 2009; 15(19): 6062-69. http://dx.doi.org/10.1158/1078-0432.CCR-09-0048

Wu C, Sim H, Huang Y, Liu Y, Hsiao S, Cheng H, et al. Overexpression of ATP-Binding Cassette Transporter ABCG2 as a Potential Mechanism of Acquired Resistance to Vemurafenib in BRAF (V600E) Mutant Cancer Cells. Biochem Pharmacol 2012.

Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R,

et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009; 323(5922): 1718-22. http://dx.doi.org/10.1126/science.1168750

Shi Z, Tiwari AK, Shukla S, Robey RW, Singh S, Kim I, et al. Sildenafil reverses ABCB1-and ABCG2-mediated chemotherapeutic drug resistance. Cancer Res 2011; 71(8): 3029-41. http://dx.doi.org/10.1158/0008-5472.CAN-10-3820

Klepsch F, Jabeen I, Chiba P, Ecker G. Pharmacoinformatic approaches to design natural product type ligands of ABC-transporters Curr Pharm Des 2010; 16(15): 1742-52. http://dx.doi.org/10.2174/138161210791163992

Robey R, Honjo Y, Morisaki K, Nadjem T, Runge S, Risbood M, et al. Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br J Cancer 2003; 89(10): 1971-78. http://dx.doi.org/10.1038/sj.bjc.6601370

Chen Z, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E, Kruh GD. Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol Pharmacol 2003; 63(2): 351-58. http://dx.doi.org/10.1124/mol.63.2.351

Rosenberg MF, Bikadi Z, Chan J, Liu X, Ni Z, Cai X, et al. The human breast cancer resistance protein (BCRP/ABCG2) shows conformational changes with mitoxantrone. Structure 2010; 18(4): 482-93. http://dx.doi.org/10.1016/j.str.2010.01.017

Robey R, Honjo Y, Morisaki K, Nadjem T, Runge S, Risbood M, et al. Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br J Cancer 2003; 89(10): 1971-78. http://dx.doi.org/10.1038/sj.bjc.6601370

Downloads

Published

2013-11-28

How to Cite

Saurabh G. Vispute, Jun-Jiang Chen, Yue-Li Sun, Kamlesh S. Sodani, Satyakam Singh, Yihang Pan, Tanaji Talele, Charles R. Ashby Jr, & Zhe-Sheng Chen. (2013). Vemurafenib (PLX4032, Zelboraf®), a BRAF Inhibitor, Modulates ABCB1-, ABCG2-, and ABCC10-Mediated Multidrug Resistance. Journal of Cancer Research Updates, 2(4),  306–317. https://doi.org/10.6000/1929-2279.2013.02.04.9

Issue

Section

Articles