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P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression.
Anticancer Res 2017; 37(12):6761-6769AR

Abstract

The present study was designed to identify conditions that could increase the sensitivity of resistant cancer cells to antimitotic drugs. We investigated whether a Janus kinase 2 (JAK2) inhibitor used in clinical trials, XL019, sensitizes antimitotic drug-resistant KBV20C cells. XL019 reduced cellular viability and increased apoptosis in vincristine-treated KBV20C cells, independently of the JAK/signal transducer and activator of transcription (STAT) pathway. Based on the ATP-binding cassette protein B1 [ABCB1, P-glycoprotein (P-gp)] inhibitory assay, we demonstrated that XL019 functions as a P-gp inhibitor in drug-resistant KBV20C cells. Considering that another JAK2 inhibitor, CEP-33779, also inhibited P-gp and sensitized drug-resistant cancer cells in a previous study, we concluded that JAK2 inhibitors can be used as P-gp inhibitors in drug-resistant cancer cells. Fluorescence-activated cell sorting, western blot, and annexin V analyses were used to further investigate the mechanism of action of XL019 in vincristine-treated KBV20C cells. XL019 induced early apoptosis of KBV20C cells in response to vincristine treatment via increased G2 phase arrest. Moreover, G2 phase arrest and apoptosis of cells co-treated with vincristine and XL019 resulted from the up-regulation of phosphorylated retinoblastoma protein (pRb), p21, and the DNA-damage protein, phosphorylated H2A histone family, member X (pH2AX). Additionally, the P-gp-inhibitory effect of XL019 was less than that of CEP-33779, and a more than 2-fold higher dose was required to sensitize vincristine-treated KBV20C cells. Furthermore, lower doses of XL019 were required to sensitize KBV20C cells to a degree similar to that obtained with the established P-gp inhibitor verapamil, suggesting that XL019 has higher specificity than verapamil. Our results showed that JAK2 inhibitors inhibited P-gp action via a direct binding mechanism, which was similar to that of verapamil. These findings indicate that JAK2 inhibitors may be promising therapeutics for the treatment of cancer that is resistant to antimitotic drugs.

Authors+Show Affiliations

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea syoon88@gmail.com hkims@skku.edu.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea syoon88@gmail.com hkims@skku.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29187454

Citation

Cheon, Ji Hyun, et al. "P-gp Inhibition By XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells With Increased P21 and pH2AX Expression." Anticancer Research, vol. 37, no. 12, 2017, pp. 6761-6769.
Cheon JH, Kim JY, Lee BM, et al. P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression. Anticancer Res. 2017;37(12):6761-6769.
Cheon, J. H., Kim, J. Y., Lee, B. M., Kim, H. S., & Yoon, S. (2017). P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression. Anticancer Research, 37(12), pp. 6761-6769.
Cheon JH, et al. P-gp Inhibition By XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells With Increased P21 and pH2AX Expression. Anticancer Res. 2017;37(12):6761-6769. PubMed PMID: 29187454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression. AU - Cheon,Ji Hyun, AU - Kim,Ji Yeong, AU - Lee,Byung-Mu, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, PY - 2017/08/24/received PY - 2017/09/21/revised PY - 2017/09/25/accepted PY - 2017/12/1/entrez PY - 2017/12/1/pubmed PY - 2017/12/20/medline KW - CEP-33779 KW - JAK2 KW - P-gp KW - XL019 KW - drug-resistance SP - 6761 EP - 6769 JF - Anticancer research JO - Anticancer Res. VL - 37 IS - 12 N2 - The present study was designed to identify conditions that could increase the sensitivity of resistant cancer cells to antimitotic drugs. We investigated whether a Janus kinase 2 (JAK2) inhibitor used in clinical trials, XL019, sensitizes antimitotic drug-resistant KBV20C cells. XL019 reduced cellular viability and increased apoptosis in vincristine-treated KBV20C cells, independently of the JAK/signal transducer and activator of transcription (STAT) pathway. Based on the ATP-binding cassette protein B1 [ABCB1, P-glycoprotein (P-gp)] inhibitory assay, we demonstrated that XL019 functions as a P-gp inhibitor in drug-resistant KBV20C cells. Considering that another JAK2 inhibitor, CEP-33779, also inhibited P-gp and sensitized drug-resistant cancer cells in a previous study, we concluded that JAK2 inhibitors can be used as P-gp inhibitors in drug-resistant cancer cells. Fluorescence-activated cell sorting, western blot, and annexin V analyses were used to further investigate the mechanism of action of XL019 in vincristine-treated KBV20C cells. XL019 induced early apoptosis of KBV20C cells in response to vincristine treatment via increased G2 phase arrest. Moreover, G2 phase arrest and apoptosis of cells co-treated with vincristine and XL019 resulted from the up-regulation of phosphorylated retinoblastoma protein (pRb), p21, and the DNA-damage protein, phosphorylated H2A histone family, member X (pH2AX). Additionally, the P-gp-inhibitory effect of XL019 was less than that of CEP-33779, and a more than 2-fold higher dose was required to sensitize vincristine-treated KBV20C cells. Furthermore, lower doses of XL019 were required to sensitize KBV20C cells to a degree similar to that obtained with the established P-gp inhibitor verapamil, suggesting that XL019 has higher specificity than verapamil. Our results showed that JAK2 inhibitors inhibited P-gp action via a direct binding mechanism, which was similar to that of verapamil. These findings indicate that JAK2 inhibitors may be promising therapeutics for the treatment of cancer that is resistant to antimitotic drugs. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/29187454/P_gp_Inhibition_by_XL019_a_JAK2_Inhibitor_Increases_Apoptosis_of_Vincristine_treated_Resistant_KBV20C_Cells_with_Increased_p21_and_pH2AX_Expression_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=29187454 DB - PRIME DP - Unbound Medicine ER -