The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine

• Published in: Biochemical and biophysical research communications Vol. 490; no. 4; pp. 1176 - 1182
• Main Authors: Cheon, Ji Hyun, Kim, Kyeong Seok, Yadav, Dharmendra Kumar, Kim, Mihyun, Kim, Hyung Sik, Yoon, Sungpil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2017
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cancer; Cell Proliferation - drug effects; CEP-33779; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Drug-resistance; Humans; JAK2; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; NVP-BSK805; P-gp; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridines - chemistry; Pyridines - pharmacology; Quinoxalines - chemistry; Quinoxalines - pharmacology; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Tumor Cells, Cultured; Vincristine - chemistry; Vincristine - pharmacology; NVP-BSK805; Fluorescence-activated cell sorting; P-gp; vincristine; Drug-resistance; CEP-33779; Dimethylsulfoxide; Verapamil; p-glycoprotein; JAK2; Cleaved ploy ADP ribose polymerase; Cancer
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.06.178

P-glycoprotein (P-gp) is overexpressed in cancer cells in order to pump out chemotherapeutic drugs, and is one of the major mechanisms responsible for multidrug resistance (MDR). It is important to identify P-gp inhibitors with low toxicity to normal cells in order to increase the efficacy of anti-cancer drugs. Previously, a JAK2 inhibitor CEP-33779 demonstrated inhibitory actions against P-gp and an ability to sensitize drug-resistant cancer cells to treatment. In the present study, we tested another JAK2 inhibitor NVP-BSK805 for P-gp inhibitory activity. In molecular docking simulation modeling, NVP-BSK805 showed higher binding affinity docking scores against a P-gp member (ABCB1) than CEP-33779 did. Furthermore, we found that lower doses of NVP-BSK805 are required to inhibit P-gp in comparison with that of CEP-33779 or verapamil (an established P-gp inhibitor) in KBV20C cells, suggesting that NVP-BSK805 has higher specificity. NVP-BSK805, CEP-33779, and verapamil demonstrated similar abilities to sensitize KBV20C cells to vincristine (VIC) treatment. Our results suggested that the JAK2 inhibitors were able to inhibit P-gp pump-action via a direct binding mechanism, similar to verapamil. However, JAK2 inhibitor-induced sensitization was not observed in VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. FACS, western-blot, and annexin V analyses were used to further investigate the mechanism of action of JAK2 inhibitors in VIC-treated KBV20C cells. Both CEP-33779 and NVP-BSK805 induced the sensitization of KBV20C cells to VIC treatment via the same mechanisms; they each caused a reduction in cell viability, increased G2 arrest, and upregulated expression of the DNA damaging protein pH2AX when used as co-treatments with VIC. These findings indicate that inhibition of JAK2 may be a promising target in the treatment of cancers that are resistant to anti-mitotic drugs. •Co-treatment of vincristine with the JAK2 inhibitors CEP-33779 and NVP-BSK805 sensitizes drug- resistant KBV20C cells.•JAK2 inhibitors directly bound to P-gp in drug-resistant KBV20C cancer cells, preventing P-gp-mediated drug efflux.•JAK2 inhibitors showed equal efficacy to the established P-gp inhibitor verapamil at comparably lower doses.•Both CEP-33779 and NVP-BSK805 are regarding as members of P-gp inhibitors.•Because they are already used in clinical trial, they may be applied to treat patients at a relatively faster pace.