{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:30:53Z","timestamp":1785547853841,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>P-glycoprotein (P-gp) overexpression is one of the major mechanisms of multidrug resistance (MDR). Previously, co-treatment with Janus kinase 2 (JAK2) inhibitors sensitized P-gp-overexpressing drug-resistant cancer cells. In this study, we assessed the cytotoxic effects of JAK2 inhibitor, fedratinib, on drug-resistant KBV20C cancer cells. We found that co-treatment with fedratinib at low doses induced cytotoxicity in KBV20C cells treated with vincristine (VIC). However, fedratinib-induced cytotoxicity was little effect on VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Fluorescence-activated cell sorting (FACS), Western blotting, and annexin V analyses were used to further investigate fedratinib\u2019s mechanism of action in VIC-treated KBV20C cells. We found that fedratinib reduced cell viability, increased G2 arrest, and upregulated apoptosis when used as a co-treatment with VIC. G2 phase arrest and apoptosis in VIC\u2013fedratinib-co-treated cells resulted from the upregulation of p21 and the DNA damaging marker pH2AX. Compared with dimethyl sulfoxide (DMSO)-treated cells, fedratinib-treated KBV20C cells showed two-fold higher P-gp-inhibitory activity, indicating that VIC\u2013fedratinib sensitization is dependent on the activity of fedratinib. Similar to VIC, fedratinib co-treatment with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) showed increased cytotoxicity in KBV20C cells. Furthermore, VIC\u2013fedratinib had similar cytotoxic effects to co-treatment with other JAK2 inhibitors (i.e., VIC\u2013CEP-33779 or VIC\u2013NVP-BSK805) at the same dose; similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is generally cytotoxic to P-gp-overexpressing resistant cancer cells. Given that fedratinib is FDA-approved, our findings support its application in the co-treatment of P-gp-overexpressing cancer patients showing MDR.<\/jats:p>","DOI":"10.3390\/ijms23094597","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T05:07:22Z","timestamp":1650604042000},"page":"4597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Yunmoon","family":"Oh","sequence":"first","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Sol","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Sun","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Hyeon","family":"Park","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7657-3970","authenticated-orcid":false,"given":"Hyung Sik","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungpil","family":"Yoon","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nrc1317","article-title":"Microtubules as a target for anticancer drugs","volume":"4","author":"Jordan","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bbrc.2011.12.141","article-title":"Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest","volume":"418","author":"Kim","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","first-page":"96","article-title":"Taxanes, microtubules and chemoresistant breast cancer","volume":"1785","author":"McGrogan","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.canlet.2015.10.010","article-title":"Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade","volume":"370","author":"Chen","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1517\/17425255.4.2.205","article-title":"Development of inhibitors of ATP-binding cassette drug transporters: Present status and challenges","volume":"4","author":"Shukla","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.5732\/cjc.013.10122","article-title":"Recent advances regarding the role of ABC subfamily C member 10 (ABCC10) in the efflux of antitumor drugs","volume":"33","author":"Kathawala","year":"2014","journal-title":"Chin. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bcp.2015.12.007","article-title":"Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein","volume":"101","author":"Chufan","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4037","DOI":"10.1182\/blood-2010-09-304311","article-title":"Dismounting the MDR horse","volume":"116","author":"Libby","year":"2010","journal-title":"Blood"},{"key":"ref_9","first-page":"137","article-title":"Recent advances in the research of P-glycoprotein inhibitors","volume":"2","author":"Yang","year":"2008","journal-title":"Biosci. Trends"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.2174\/15680266113136660159","article-title":"New therapeutic bearings for repositioned drugs","volume":"13","author":"Clark","year":"2013","journal-title":"Curr. Top Med. Chem."},{"key":"ref_11","first-page":"ed40","article-title":"Recycling existing drugs for cancer therapy: Delivering low cost cancer care","volume":"8","author":"Pantziarka","year":"2014","journal-title":"Ecancermedicalscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"632657","DOI":"10.3389\/fonc.2021.632657","article-title":"Editorial: FDA-Approved drug repositioning for P-glycoprotein overexpressing resistant cancer","volume":"11","author":"Yoon","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1097\/IGC.0000000000000550","article-title":"Inhibition of JAK2 reverses paclitaxel resistance in human ovarian cancer cells","volume":"25","author":"Xu","year":"2015","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"334ra53","DOI":"10.1126\/scitranslmed.aad3001","article-title":"Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence","volume":"8","author":"Balko","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26483","DOI":"10.18632\/oncotarget.4494","article-title":"Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer","volume":"6","author":"Barrett","year":"2015","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/onc.2015.150","article-title":"Targeting JAK kinase in solid tumors: Emerging opportunities and challenges","volume":"35","author":"Buchert","year":"2016","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e424","DOI":"10.1097\/HS9.0000000000000424","article-title":"JAK inhibition for the treatment of myelofibrosis: Limitations and future perspectives","volume":"4","author":"Bose","year":"2020","journal-title":"Hemasphere"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Raivola, J., Haikarainen, T., Abraham, B.G., and Silvennoinen, O. (2021). Janus Kinases in Leukemia. Cancers, 13.","DOI":"10.3390\/cancers13040800"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.bcp.2014.07.008","article-title":"CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function","volume":"91","author":"Tang","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","first-page":"6761","article-title":"P-gp inhibition by XL019, a JAK2 inhibitor, Increases apoptosis of vincristine-treated resistant KBV20C cells with increased p21 and pH2AX expression","volume":"37","author":"Cheon","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.bbrc.2017.06.178","article-title":"The JAK2 inhibitors CEP-33779 and NVP-BSK805 have high P-gp inhibitory activity and sensitize drug-resistant cancer cells to vincristine","volume":"490","author":"Cheon","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2217\/fon-2019-0612","article-title":"Current and future role of fedratinib in the treatment of myelofibrosis","volume":"16","author":"Ragheb","year":"2020","journal-title":"Future Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41375-020-0954-2","article-title":"Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis","volume":"35","author":"Talpaz","year":"2021","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/978-1-4939-3542-0_25","article-title":"Anti-Microtubule Drugs","volume":"1413","author":"Florian","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"687","DOI":"10.21873\/anticanres.14820","article-title":"A low dose of aripiprazole has the strongest sensitization effect among 19 repositioned bipolar drugs in P-gp-overexpressing drug-resistant cancer cells","volume":"41","author":"Jiang","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"696","DOI":"10.3389\/fonc.2020.00696","article-title":"Low-dose crizotinib, a tyrosine kinase inhibitor, highly and specifically sensitizes P-glycoprotein-overexpressing chemoresistant cancer cells through induction of late apoptosis in vivo and in vitro","volume":"10","author":"Kim","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.7150\/ijbs.59855","article-title":"Specific pyruvate kinase M2 inhibitor, compound 3K, Induces autophagic cell death through disruption of the glycolysis pathway in ovarian cancer cells","volume":"17","author":"Park","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s002800050989","article-title":"The effect of antimicrotubule agents on signal transduction pathways of apoptosis: A review","volume":"44","author":"Wang","year":"1999","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5063","DOI":"10.21873\/anticanres.11075","article-title":"Co-treatment with celecoxib or NS398 strongly sensitizes resistant cancer cells to antimitotic drugs independent of P-gp inhibition","volume":"36","author":"Lim","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5101","DOI":"10.21873\/anticanres.12830","article-title":"Low doses of the anti-psychotic drug aripiprazole have strong P-gp-inhibitory activity and sensitize anti-mitotic drug-resistant cancer cells","volume":"38","author":"Kim","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1177\/108705710200700105","article-title":"Microplate screening of the differential effects of test agents on Hoechst 33342, rhodamine 123, and rhodamine 6G accumulation in breast cancer cells that overexpress P-glycoprotein","volume":"7","author":"Sarver","year":"2002","journal-title":"J. Biomol. Screen"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5685","DOI":"10.21873\/anticanres.12905","article-title":"P-gp inhibition by the anti-psychotic drug pimozide increases apoptosis, as well as expression of pRb and pH2AX in highly drug-resistant KBV20C cells","volume":"38","author":"Kim","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_33","first-page":"4139","article-title":"Highly eribulin-resistant KBV20C oral cancer cells can be sensitized by co-treatment with the third-generation P-glycoprotein inhibitor, elacridar, at a low dose","volume":"37","author":"Park","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5867","DOI":"10.21873\/anticanres.11172","article-title":"Highly halaven-resistant KBV20C cancer cells can be sensitized by co-treatment with fluphenazine","volume":"36","author":"Cheon","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.21873\/anticanres.11171","article-title":"Anti-malarial drugs primaquine and chloroquine have different sensitization effects with anti-mitotic drugs in resistant cancer cells","volume":"36","author":"Choi","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"82","DOI":"10.12688\/f1000research.13167.1","article-title":"JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders","volume":"7","author":"Vainchenker","year":"2018","journal-title":"F1000Res"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s11899-020-00596-z","article-title":"The next generation of JAK inhibitors: An update on fedratinib, momelotonib, and pacritinib","volume":"15","author":"Patel","year":"2020","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Oh, Y., Lee, J.S., Lee, J.S., Park, J.H., Kim, H.S., and Yoon, S. Co-treatment of low dose pacritinib, a phase III JAK2 inhibitor, greatly increases apoptosis of P-gp over-expessing cancer cells with multidrug resistance. Anticancer Res., 2022. in press.","DOI":"10.21873\/anticanres.15722"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3785","DOI":"10.21873\/anticanres.13527","article-title":"Tyrosine kinase inhibitors imatinib and erlotinib increase apoptosis of antimitotic drug-resistant KBV20C cells without inhibiting P-gp","volume":"39","author":"Kim","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.21873\/anticanres.13525","article-title":"Histamine receptor antagonists, loratadine and azelastine, sensitize P-gp-overexpressing antimitotic drug-resistant KBV20C cells through different molecular mechanisms","volume":"39","author":"Kim","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.21873\/anticanres.13524","article-title":"Co-treatment with HIV protease inhibitor nelfinavir creatly increases late-phase apoptosis of drug-resistant KBV20C cancer cells independently of P-glycoprotein inhibition","volume":"39","author":"Kim","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"807","DOI":"10.3892\/ijo.2010.879","article-title":"HDAC inhibitors downregulate MRP2 expression in multidrug resistant cancer cells: Implication for chemosensitization","volume":"38","author":"Kim","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6179","DOI":"10.21873\/anticanres.15437","article-title":"Sensitization effects of pepurposed blood pressure-regulating drugs on drug-resistant cancer cells","volume":"41","author":"Jiang","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5149","DOI":"10.21873\/anticanres.12837","article-title":"Aging-related repositioned drugs, donepezil and sildenafil citrate, increase apoptosis of anti-mitotic drug-resistant KBV20C cells through different molecular mechanisms","volume":"38","author":"Kim","year":"2018","journal-title":"Anticancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:58:11Z","timestamp":1760137091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,21]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23094597"],"URL":"https:\/\/doi.org\/10.3390\/ijms23094597","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,21]]}}}