{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:46:27Z","timestamp":1784544387412,"version":"3.55.0"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2020-04046"],"award-info":[{"award-number":["RGPIN-2020-04046"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["168913"],"award-info":[{"award-number":["168913"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Tyrosine kinase inhibitors (TKI) are often used in combination with other chemotherapeutic nucleoside\/nucleobase analogues, such as gemcitabine and 6-mercaptopurine, in the treatment of various cancers. Past studies have shown that several TKI inhibit the cellular uptake of nucleoside analogues by the equilibrative nucleoside transporter subtype 1 (ENT1), and suggest that TKI may also inhibit other related nucleoside and nucleobase transporters such as ENT2 and the equilibrative nucleobase transporter (ENBT1). To assess this possibility in a controlled manner, we have compared the ability of a series of TKI to inhibit each of these transporters in HEK293 cells that have been genetically modified to express either ENT1, ENT2 or ENBT1 in isolation, and on ENBT1 natively expressed in the chronic myeloid leukemia cell line K562. All TKI tested inhibited ENT1 and ENT2 with K\n                    <jats:sub>i<\/jats:sub>\n                    values ranging from 1 to 30 \u00b5M, typically with higher affinities for ENT1 than for ENT2. Gefitinib, which was one of the most effective inhibitors of ENT1, also inhibited ENBT1 with a similar affinity. The loss or gain of these transporters had no impact on the ability of gefitinib to directly affect cell viability, indicating that they were unlikely to be involved in the cellular uptake of the TKI. These data suggest that TKI inhibit multiple purine transporters, likely via interactions with their common purine ring binding domain. However, interactions between TKI and other nucleoside\/nucleobase analogue drugs that are substrates for these systems are not likely to be a significant concern at the doses commonly used therapeutically.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0348426","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:29:12Z","timestamp":1778866152000},"page":"e0348426","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of purine nucleoside and nucleobase transporters by tyrosine kinase inhibitors"],"prefix":"10.1371","volume":"21","author":[{"given":"Nayiar","family":"Shahid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan H.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerrylei B.","family":"Jabilona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh H.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Ruel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9006-7529","authenticated-orcid":true,"given":"James R.","family":"Hammond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"pone.0348426.ref001","doi-asserted-by":"crossref","first-page":"100825","DOI":"10.1016\/j.blre.2021.100825","article-title":"Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions","volume":"49","author":"AEG Osman","year":"2021","journal-title":"Blood Rev"},{"issue":"3","key":"pone.0348426.ref002","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3324\/haematol.2015.124016","article-title":"Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia","volume":"100","author":"V Leoni","year":"2015","journal-title":"Haematologica"},{"key":"pone.0348426.ref003","doi-asserted-by":"crossref","first-page":"100195","DOI":"10.1016\/j.medidd.2024.100195","article-title":"Recent developments in receptor tyrosine kinase inhibitors: A promising mainstay in targeted cancer therapy","volume":"23","author":"R Kumar","year":"2024","journal-title":"Med Drug Discov"},{"issue":"6","key":"pone.0348426.ref004","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1124\/mol.118.114389","article-title":"Characterization of 6-Mercaptopurine Transport by the SLC43A3-Encoded Nucleobase Transporter","volume":"95","author":"NM Ruel","year":"2019","journal-title":"Mol Pharmacol"},{"key":"pone.0348426.ref005","doi-asserted-by":"crossref","first-page":"115741","DOI":"10.1016\/j.bcp.2023.115741","article-title":"Nucleoside-based anticancer drugs: Mechanism of action and drug resistance","volume":"215","author":"L Hruba","year":"2023","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"pone.0348426.ref006","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3390\/pharmaceutics15020364","article-title":"The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy","volume":"15","author":"E Puris","year":"2023","journal-title":"Pharmaceutics"},{"issue":"5","key":"pone.0348426.ref007","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00280-015-2859-8","article-title":"Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors","volume":"76","author":"VL Damaraju","year":"2015","journal-title":"Cancer Chemother Pharmacol"},{"key":"pone.0348426.ref008","doi-asserted-by":"crossref","first-page":"15057","DOI":"10.1038\/srep15057","article-title":"Functional identification of SLC43A3 as an equilibrative nucleobase transporter involved in purine salvage in mammals","volume":"5","author":"J Furukawa","year":"2015","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0348426.ref009","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1124\/jpet.122.001155","article-title":"Impact of SLC43A3\/ENBT1 expression and function on 6-mercaptopurine transport and cytotoxicity in human acute lymphoblastic leukemia cells","volume":"382","author":"NM Ruel","year":"2022","journal-title":"J Pharmacol Exp Ther"},{"issue":"5","key":"pone.0348426.ref010","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s13318-021-00703-2","article-title":"Differential inhibition of equilibrative nucleoside transporter 1 (ENT1) activity by tyrosine kinase inhibitors","volume":"46","author":"E Jouan","year":"2021","journal-title":"Eur J Drug Metab Pharmacokinet"},{"issue":"2","key":"pone.0348426.ref011","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1124\/jpet.102.044214","article-title":"Inhibition of nucleoside transport by protein kinase inhibitors","volume":"304","author":"M Huang","year":"2003","journal-title":"J Pharmacol Exp Ther"},{"issue":"1","key":"pone.0348426.ref012","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1158\/1078-0432.CCR-13-2293","article-title":"Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity","volume":"20","author":"VL Damaraju","year":"2014","journal-title":"Clin Cancer Res"},{"issue":"36","key":"pone.0348426.ref013","doi-asserted-by":"crossref","first-page":"18809","DOI":"10.1074\/jbc.M116.741074","article-title":"Selective Inhibition of Human Equilibrative and Concentrative Nucleoside Transporters by BCR-ABL Kinase Inhibitors: IDENTIFICATION OF KEY hENT1 AMINO ACID RESIDUES FOR INTERACTION WITH BCR-ABL KINASE INHIBITORS","volume":"291","author":"VL Damaraju","year":"2016","journal-title":"J Biol Chem"},{"issue":"10","key":"pone.0348426.ref014","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1124\/dmd.124.001814","article-title":"Development of a Novel HEK293 Cell Model Lacking SLC29A1 to Study the Pharmacology of Endogenous SLC29A2-Encoded Equilibrative Nucleoside Transporter Subtype 2","volume":"52","author":"N Shahid","year":"2024","journal-title":"Drug Metab Dispos"},{"issue":"12","key":"pone.0348426.ref015","doi-asserted-by":"crossref","first-page":"100203","DOI":"10.1016\/j.dmd.2025.100203","article-title":"Characterization of genetically modified human embryonic kidney 293 cells lacking equilibrative nucleoside transporter subtype 2, or both subtypes 1 and 2, and the impact of their loss on sensitivity to chemotherapeutic purine\/pyrimidine analogs","volume":"53","author":"N Shahid","year":"2025","journal-title":"Drug Metab Dispos"},{"issue":"10","key":"pone.0348426.ref016","article-title":"Functional comparison of human and murine equilibrative nucleobase transporter 1","volume":"19","author":"CS Kim","year":"2024","journal-title":"PLoS One"},{"issue":"23","key":"pone.0348426.ref017","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction","volume":"22","author":"Y Cheng","year":"1973","journal-title":"Biochem Pharmacol"},{"issue":"2","key":"pone.0348426.ref018","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/clpt.2009.208","article-title":"Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib","volume":"87","author":"C Tanaka","year":"2010","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0348426.ref019","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.lungcan.2016.01.005","article-title":"Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer","volume":"93","author":"T Hirose","year":"2016","journal-title":"Lung Cancer"},{"issue":"4","key":"pone.0348426.ref020","first-page":"165","article-title":"Comparative pharmacokinetic evaluation and bioequivalence study of three different formulations of Imatinib Mesylate in CML patients","volume":"9","author":"E Mohajeri","year":"2015","journal-title":"Int J Hematol Oncol Stem Cell Res"},{"key":"pone.0348426.ref021","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.2147\/DDDT.S521260","article-title":"Dasatinib Dose Optimization Based on Therapeutic Drug Monitoring in Patients with Chronic-Phase Chronic Myeloid Leukemia","volume":"19","author":"F Cheng","year":"2025","journal-title":"Drug Des Devel Ther"},{"issue":"3","key":"pone.0348426.ref022","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.lungcan.2015.06.011","article-title":"Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction","volume":"89","author":"M Das","year":"2015","journal-title":"Lung Cancer"},{"issue":"9","key":"pone.0348426.ref023","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1097\/JTO.0b013e31825cca1c","article-title":"Sunitinib plus erlotinib for the treatment of advanced\/metastatic non-small-cell lung cancer: a lead-in study","volume":"7","author":"Jr Blumenschein GR","year":"2012","journal-title":"J Thorac Oncol"},{"issue":"11","key":"pone.0348426.ref024","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1681\/ASN.2014080793","article-title":"EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy","volume":"26","author":"N Liu","year":"2015","journal-title":"J Am Soc Nephrol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348426","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:29:18Z","timestamp":1778866158000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348426"}},"subtitle":[],"editor":[{"given":"Ot\u00e1vio Augusto","family":"Chaves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":24,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0348426","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}