{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:20:52Z","timestamp":1787062852128,"version":"build-2736575974"},"reference-count":66,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CONACYT (Mexico City, Mexico)","award":["142062"],"award-info":[{"award-number":["142062"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20\u201330% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 \u03bcM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib.<\/jats:p>","DOI":"10.3390\/ijms23147715","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T23:02:01Z","timestamp":1657666921000},"page":"7715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Omar","family":"Prado-Carrillo","sequence":"first","affiliation":[{"name":"Laboratorio de F\u00e1rmaco-Oncolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"},{"name":"Posgrado en Ciencias Bioqu\u00edmicas, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Ciudad de Mexico 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abner","family":"Arenas-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Laboratorio de F\u00e1rmaco-Oncolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9361-4834","authenticated-orcid":false,"given":"Monserrat","family":"Llaguno-Munive","sequence":"additional","affiliation":[{"name":"Laboratorio de F\u00e1rmaco-Oncolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Jurado","sequence":"additional","affiliation":[{"name":"Laboratorio de F\u00e1rmaco-Oncolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5766-2684","authenticated-orcid":false,"given":"Jazmin","family":"P\u00e9rez-Rojas","sequence":"additional","affiliation":[{"name":"Laboratorio de F\u00e1rmaco-Oncolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Cervera-Ceballos","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Docencia, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1759-7686","authenticated-orcid":false,"given":"Patricia","family":"Garcia-Lopez","sequence":"additional","affiliation":[{"name":"Laboratorio de F\u00e1rmaco-Oncolog\u00eda, Subdirecci\u00f3n de Investigaci\u00f3n B\u00e1sica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/S0140-6736(21)01204-6","article-title":"Chronic myeloid leukaemia","volume":"398","author":"Cortes","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/S0140-6736(13)62120-0","article-title":"Chronic myeloid leukaemia","volume":"385","author":"Apperley","year":"2015","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1159\/000140633","article-title":"BCR-ABL in chronic myelogenous leukemia\u2014how does it work?","volume":"119","author":"Goldman","year":"2008","journal-title":"Acta Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40880-016-0108-0","article-title":"The Philadelphia chromosome in leukemogenesis","volume":"35","author":"Kang","year":"2016","journal-title":"Chin. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Di Felice, E., Roncaglia, F., Venturelli, F., Mangone, L., Luminari, S., Cirilli, C., Carrozzi, G., and Giorgi Rossi, P. (2018). The impact of introducing tyrosine kinase inhibitors on chronic myeloid leukemia survival: A population-based study. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4984-3"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nm0596-561","article-title":"Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells","volume":"2","author":"Druker","year":"1996","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1056\/NEJM200104053441401","article-title":"Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia","volume":"344","author":"Druker","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/sj.leu.2402912","article-title":"Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies","volume":"17","author":"Clarkson","year":"2003","journal-title":"Leukemia"},{"key":"ref_9","first-page":"152","article-title":"Chronic myeloid leukemia in 2006: A perspective","volume":"91","author":"Mauro","year":"2006","journal-title":"Chronic. Myeloid. Leuk."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s10147-007-0699-1","article-title":"The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias","volume":"12","author":"Maekawa","year":"2007","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_11","first-page":"77","article-title":"Clinical pharmacokinetics of imatinib mesylate","volume":"19","author":"Leveque","year":"2005","journal-title":"Vivo"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1007\/s11095-014-1389-0","article-title":"ABC transporters in multi-drug resistance and ADME-Tox of small molecule tyrosine kinase inhibitors","volume":"31","author":"Deng","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.1472-8206.2004.00291.x","article-title":"Functional interaction of intestinal CYP3A4 and P-glycoprotein","volume":"18","author":"Niemi","year":"2004","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3634","DOI":"10.1182\/blood-2011-03-341073","article-title":"SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia","volume":"118","author":"Esposito","year":"2011","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1177\/107327480901600204","article-title":"Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia","volume":"16","author":"Kantarjian","year":"2009","journal-title":"Cancer Control."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.critrevonc.2014.11.001","article-title":"Mechanisms of resistance to BCR-ABL TKIs and the therapeutic strategies: A review","volume":"93","author":"Yang","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Maia, R.C., Vasconcelos, F.C., Souza, P.S., and Rumjanek, V.M. (2018). Towards Comprehension of the ABCB1\/P-Glycoprotein Role in Chronic Myeloid Leukemia. Molecules, 23.","DOI":"10.3390\/molecules23010119"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1182\/blood-2003-12-4276","article-title":"Active transport of imatinib into and out of cells: Implications for drug resistance","volume":"104","author":"Thomas","year":"2004","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2014.11.013","article-title":"Modulation of P-glycoprotein efflux pump: Induction and activation as a therapeutic strategy","volume":"149","author":"Silva","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1007\/s00280-004-0832-z","article-title":"Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects","volume":"54","author":"Dutreix","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4082\/kjfm.2015.36.5.197","article-title":"An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians","volume":"36","author":"Granatowicz","year":"2015","journal-title":"Korean J. Fam. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1002\/ajh.25011","article-title":"Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring","volume":"93","author":"Jabbour","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"825","DOI":"10.2147\/DDDT.S191303","article-title":"Chronic myelogenous leukemia, a still unsolved problem: Pitfalls and new therapeutic possibilities","volume":"13","author":"Flis","year":"2019","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/ajh.25792","article-title":"Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring","volume":"95","author":"Jabbour","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1586\/14737140.2014.924400","article-title":"Bosutinib: A third generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia","volume":"14","author":"Hill","year":"2014","journal-title":"Expert. Rev. Anticancer. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.1182\/blood-2008-12-196543","article-title":"Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study","volume":"113","author":"Noens","year":"2009","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1200\/JCO.2009.26.3087","article-title":"Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib","volume":"28","author":"Marin","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1056\/NEJM200104053441402","article-title":"Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome","volume":"344","author":"Druker","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1590\/S0001-37652001000100007","article-title":"Multidrug resistance in tumour cells: Characterization of the multidrug resistant cell line K562-Lucena 1","volume":"73","author":"Rumjanek","year":"2001","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110","DOI":"10.5732\/cjc.011.10327","article-title":"Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells","volume":"31","author":"Peng","year":"2012","journal-title":"Chin. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.leukres.2014.12.008","article-title":"Drug transporters play a key role in the complex process of Imatinib resistance in vitro","volume":"39","author":"Alves","year":"2015","journal-title":"Leuk. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e23374","DOI":"10.1002\/jcla.23374","article-title":"Overexpression of P-glycoprotein and resistance to Imatinib in chronic myeloid leukemia patients","volume":"34","author":"Ammar","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1248\/bpb.28.316","article-title":"In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats","volume":"28","author":"Kageyama","year":"2005","journal-title":"Biol. Pharm. Bull."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0022-5347(17)34999-6","article-title":"Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells","volume":"151","author":"Siegsmund","year":"1994","journal-title":"J. Urol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1128\/AAC.46.1.160-165.2002","article-title":"Interaction of common azole antifungals with P glycoprotein","volume":"46","author":"Wang","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.3892\/ijo.2016.3611","article-title":"Inhibition of pregnane X receptor pathway contributes to the cell growth inhibition and apoptosis of anticancer agents in ovarian cancer cells","volume":"49","author":"Masuyama","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1128\/AAC.30.2.206","article-title":"Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers","volume":"30","author":"Huang","year":"1986","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/87912","article-title":"The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux","volume":"7","author":"Synold","year":"2001","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1158\/1078-0432.CCR-06-1592","article-title":"Activated pregnenolone X-receptor is a target for ketoconazole and its analogs","volume":"13","author":"Wang","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1124\/dmd.107.018341","article-title":"Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression","volume":"36","author":"Svecova","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"494","DOI":"10.4062\/biomolther.2018.042","article-title":"Imidazole Antifungal Drugs Inhibit the Cell Proliferation and Invasion of Human Breast Cancer Cells","volume":"26","author":"Bae","year":"2018","journal-title":"Biomol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1006\/taap.1998.8467","article-title":"Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines","volume":"153","author":"Ho","year":"1998","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jhep.2018.09.022","article-title":"Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma","volume":"70","author":"Chen","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"38915","DOI":"10.1074\/jbc.M206855200","article-title":"Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2","volume":"277","author":"Patel","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.leukres.2007.11.007","article-title":"Imatinib-resistant K562 cells are more sensitive to celecoxib, a selective COX-2 inhibitor: Role of COX-2 and MDR-1","volume":"32","author":"Arunasree","year":"2008","journal-title":"Leuk. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/j.1875-9114.1984.tb03398.x","article-title":"Ketoconazole. Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use","volume":"4","year":"1984","journal-title":"Pharmacotherapy"},{"key":"ref_47","unstructured":"Brunton, L.L., Hilal-Dandan, R., and Knollmann, B.C. (2018). Goodman & Gilman\u2019s: The Pharmacological Basis of Therapeutics, McGraw Hill. [13th ed.]."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10200","DOI":"10.1038\/s41598-021-89655-w","article-title":"Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma","volume":"11","author":"Greenberg","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.31557\/APJCP.2021.22.10.3101","article-title":"Ketoconazole for the Treatment of Docetaxel-Naive Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Systematic Review","volume":"22","author":"Tresnanda","year":"2021","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_50","first-page":"891","article-title":"Inhibition of proliferation and migration of melanoma cells by ketoconazole and Ganoderma immunomodulatory proteins","volume":"18","author":"Lu","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s12672-019-00361-6","article-title":"Effects of Ketoconazole on ACTH-Producing and Non-ACTH-Producing Neuroendocrine Tumor Cells","volume":"10","author":"Feelders","year":"2019","journal-title":"Horm. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1080\/15548627.2019.1569934","article-title":"A novel role for ketoconazole in hepatocellular carcinoma treatment: Linking PTGS2 to mitophagy machinery","volume":"15","author":"Chen","year":"2019","journal-title":"Autophagy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1158\/1078-0432.CCR-18-1854","article-title":"Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells","volume":"25","author":"Agnihotri","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1200\/JCO.2004.06.037","article-title":"Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583)","volume":"22","author":"Small","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1002\/jcph.795","article-title":"No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies","volume":"56","author":"Outeiro","year":"2016","journal-title":"J. Clin. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"891336","DOI":"10.3389\/fphar.2022.891336","article-title":"Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database","volume":"13","author":"Zhou","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_57","first-page":"e18940","article-title":"Systematic Review of Antifungal-Induced Acute Liver Failure","volume":"13","author":"Gadour","year":"2022","journal-title":"Cureus"},{"key":"ref_58","first-page":"149","article-title":"Clinical hepatotoxicity associated with antifungal agents","volume":"16","author":"Kyriakidis","year":"2017","journal-title":"Expert. Opin. Drug Saf."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3389\/fonc.2017.00273","article-title":"Giving Drugs a Second Chance: Overcoming Regulatory and Financial Hurdles in Repurposing Approved Drugs As Cancer Therapeutics","volume":"7","author":"Hernandez","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_61","first-page":"419","article-title":"Clinical approach to circumvention of multidrug resistance in refractory leukemic patients: Association of cyclosporin A with etoposide","volume":"16","author":"Maia","year":"1997","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1182\/blood.V100.5.1910.h81702001910_1910_1912","article-title":"Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase","volume":"100","author":"List","year":"2002","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1159\/000495650","article-title":"Targeting P-Glycoprotein: Nelfinavir Reverses Adriamycin Resistance in K562\/ADR Cells","volume":"51","author":"Liu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Alves, R., Gon\u00e7alves, A.C., Jorge, J., Almeida, A.M., and Sarmento-Ribeiro, A.B. (2022). Combination of Elacridar with Imatinib Modulates Resistance Associated with Drug Efflux Transporters in Chronic Myeloid Leukemia. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051158"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"106523","DOI":"10.1016\/j.leukres.2021.106523","article-title":"Assessment of azithromycin as an anticancer agent for treatment of imatinib sensitive and resistant CML cells","volume":"102","author":"Ozkan","year":"2021","journal-title":"Leuk. Res."},{"key":"ref_66","unstructured":"Motulsky, H.J. (2016, March 05). GraphPad Curve Fitting Guide. Available online: http:\/\/www.graphpad.com\/guides\/prism\/7\/curve-fitting\/index.htm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7715\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:49:12Z","timestamp":1760140152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,13]]},"references-count":66,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147715"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147715","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,13]]}}}