Details

Autor(en) / Beteiligte

• Cheon, Ji Hyun
• Kim, Kyeong Seok
• Yadav, Dharmendra Kumar
• Kim, Mihyun
• Kim, Hyung Sik
• Yoon, Sungpil

Titel

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

Ist Teil von

• Biochemical and biophysical research communications, 2017-09, Vol.490 (4), p.1176-1182

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

ScienceDirect Journals (5 years ago - present)

Beschreibungen/Notizen

• 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.