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The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine.
Biochem Biophys Res Commun 2017; 490(4):1176-1182BB

Abstract

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.

Authors+Show Affiliations

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: hkims@skku.edu.School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: syoon88@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28669723

Citation

Cheon, Ji Hyun, et al. "The JAK2 Inhibitors CEP-33779 and NVP-BSK805 Have High P-gp Inhibitory Activity and Sensitize Drug-resistant Cancer Cells to Vincristine." Biochemical and Biophysical Research Communications, vol. 490, no. 4, 2017, pp. 1176-1182.
Cheon JH, Kim KS, Yadav DK, et al. The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine. Biochem Biophys Res Commun. 2017;490(4):1176-1182.
Cheon, J. H., Kim, K. S., Yadav, D. K., Kim, M., Kim, H. S., & Yoon, S. (2017). The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine. Biochemical and Biophysical Research Communications, 490(4), pp. 1176-1182. doi:10.1016/j.bbrc.2017.06.178.
Cheon JH, et al. The JAK2 Inhibitors CEP-33779 and NVP-BSK805 Have High P-gp Inhibitory Activity and Sensitize Drug-resistant Cancer Cells to Vincristine. Biochem Biophys Res Commun. 2017 09 2;490(4):1176-1182. PubMed PMID: 28669723.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine. AU - Cheon,Ji Hyun, AU - Kim,Kyeong Seok, AU - Yadav,Dharmendra Kumar, AU - Kim,Mihyun, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, Y1 - 2017/06/29/ PY - 2017/06/23/received PY - 2017/06/28/accepted PY - 2017/7/4/pubmed PY - 2017/9/22/medline PY - 2017/7/4/entrez KW - CEP-33779 KW - Cancer KW - Drug-resistance KW - JAK2 KW - NVP-BSK805 KW - P-gp SP - 1176 EP - 1182 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 490 IS - 4 N2 - 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. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/28669723/The_JAK2_inhibitors_CEP_33779_and_NVP_BSK805_have_high_P_gp_inhibitory_activity_and_sensitize_drug_resistant_cancer_cells_to_vincristine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(17)31309-8 DB - PRIME DP - Unbound Medicine ER -