The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study

// Rishil J. Kathawala 1,8,* , Liuya Wei 1,2,* , Nagaraju Anreddy 1 , Kang Chen 3,4,5,6 , Atish Patel 1 , Saeed Alqahtani 7 , Yun-Kai Zhang 1 , Yi-Jun Wang 1 , Kamlesh Sodani 1 , Amal Kaddoumi 7 , Charles R. Ashby Jr. 1 and Zhe-Sheng Chen 1 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA 2 School of Pharmacy and Biological Sciences, Weifang Medical University, Weifang, People’s Republic of China 3 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA 4 Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA 5 Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA 6 Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA 7 Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana, Monroe, LA, USA 8 Current address: Division of Oncology, Stanford University, Stanford, CA, USA * These authors contributed equally to the work Correspondence: Zhe-Sheng Chen, email: // Charles R. Ashby Jr., email: // Keywords : NVP-BHG712; ABCC10; ABC transporters; Paclitaxel; Tyrosine kinase inhibitors Received : September 05, 2014 Accepted : October 28, 2014 Published : October 28, 2014 Abstract Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 μM), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter.