{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:55:25Z","timestamp":1781762125184,"version":"3.54.5"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Multidrug resistance (MDR) remains a major challenge in cancer treatment, as it is a significant factor contributing to chemotherapy failure and cancer recurrence. Among various resistance mechanisms, the overexpression of the breast cancer resistance protein (BCRP\/ABCG2) has been identified as a cause of MDR in multiple cancers, including breast cancer, lung cancer, and colon cancer (S)-SAR131675 is the S-enantiomer of SAR131675 (HY-15458), which significantly and selectively suppresses the Vascular Endothelial Growth Factor Receptor 3 (VEGFR3). In this research (S)-SAR131675 shows the ability to overcome the ABCG2-mediated MDR in both the non-small cell lung cancer cell line NCI-H460 and its ABCG2-overexpressing cell line NCI-H460\/TPT10, as well as the colorectal cancer cell line S1 and its ABCG2-overexpressing cell line S1-M1-80. Through several experiments, we demonstrate that (S)-SAR131675 targets the efflux function of ABCG2, resulting in an increased intracellular concentration of substrates of ABCG2, including mitoxantrone and topotecan. Additionally, this resensitizing effect did not affect the overall protein expression or subcellular localization of ABCG2 in the ABCG2-overexpressing cell lines. In summary (S)-SAR131675 can overcome ABCG2-mediated MDR by directly suppressing the drug efflux function, providing a promising basis for the further development of cancer treatments associated with MDR in the future.<\/jats:p>","DOI":"10.3389\/fphar.2026.1857174","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:34:53Z","timestamp":1781760893000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reversal of ABCG2-mediated MDR by VEGFR3 inhibitor (S)-SAR131675"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["Queens, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqian","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology, NHC Key Laboratory of Molecular Probe and Targeted Theragnostic, Harbin Medical University Cancer Hospital","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["Queens, NY, United States"]},{"name":"Perlmutter Cancer Center, NYU Langone Health","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Duo","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["Queens, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["Queens, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu-Xu","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["Queens, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, NHC Key Laboratory of Molecular Probe and Targeted Theragnostic, Harbin Medical University Cancer Hospital","place":["Harbin, China"]},{"name":"Department of Cystoscope Center, Harbin Medical University Cancer Hospital","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["Queens, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1158\/1535-7163.MCT-11-0866-T","article-title":"SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities","volume":"11","author":"Alam","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1038\/nm.2545","article-title":"The lymphatic vasculature in disease","volume":"17","author":"Alitalo","year":"2011","journal-title":"Nat. Med."},{"key":"B3","first-page":"417","article-title":"Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C","volume":"1","author":"Allen","year":"2002","journal-title":"Mol. Cancer Ther."},{"key":"B4","first-page":"5337","article-title":"A human placenta-specific ATP-Binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance","volume":"58","author":"Allikmets","year":"1998","journal-title":"Cancer Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.cancergen.2025.12.001","article-title":"Genetic modulation of ABCB1: sunvozertinib reverses ABCB1-mediated multidrug resistance in cancer cells","author":"Cao","year":"2026","journal-title":"Cancer Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1158\/1078-0432.CCR-11-1590","article-title":"Molecular pathways: regulation and therapeutic implications of multidrug resistance","volume":"18","author":"Chen","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","first-page":"640656","DOI":"10.3389\/fonc.2021.640656","article-title":"Overexpression of ABCC1 confers drug resistance to betulin","volume":"11","author":"Chen","year":"2021","journal-title":"Front. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1400699","DOI":"10.3389\/fphar.2024.1400699","article-title":"Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells","volume":"15","author":"Chen","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.canlet.2018.10.020","article-title":"Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: in vitro and in vivo","volume":"442","author":"De Vera","year":"2019","journal-title":"Cancer Lett."},{"key":"B11","doi-asserted-by":"publisher","first-page":"865","DOI":"10.3389\/fcell.2020.00865","article-title":"Bruton's tyrosine kinase (BTK) inhibitor RN486 overcomes ABCB1-Mediated multidrug resistance in cancer cells","volume":"8","author":"Dong","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"288","DOI":"10.2478\/jtim-2024-0011","article-title":"RN486, a Bruton's tyrosine kinase inhibitor, antagonizes multidrug resistance in ABCG2-overexpressing cancer cells","volume":"12","author":"Dong","year":"","journal-title":"J. Transl. Int. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"217309","DOI":"10.1016\/j.canlet.2024.217309","article-title":"Mobocertinib antagonizes multidrug resistance in ABCB1- and ABCG2-overexpressing cancer cells: in vitro and in vivo studies","volume":"607","author":"Dong","year":"","journal-title":"Cancer Lett."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1056\/NEJMoa0707330","article-title":"VEGF inhibition and renal thrombotic microangiopathy","volume":"358","author":"Eremina","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/s41571-025-01059-1","article-title":"Understanding and overcoming multidrug resistance in cancer","volume":"22","author":"Ge","year":"2025","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1124\/dmd.108.022046","article-title":"Substrate-dependent breast cancer resistance protein (Bcrp1\/Abcg2)-Mediated interactions: consideration of multiple binding sites in in vitro assay design","volume":"37","author":"Giri","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"B17","doi-asserted-by":"publisher","first-page":"126","DOI":"10.5732\/cjc.011.10315","article-title":"Reversing multidrug resistance by tyrosine kinase inhibitors","volume":"31","author":"He","year":"2012","journal-title":"Chin. J. Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/s0925-4439(02)00095-9","article-title":"Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1","volume":"1587","author":"Hegedus","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"B19","doi-asserted-by":"publisher","first-page":"6062","DOI":"10.1158\/1078-0432.CCR-09-0048","article-title":"Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-Binding cassette transporters","volume":"15","author":"Hu","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"a006502","DOI":"10.1101\/cshperspect.a006502","article-title":"Signal transduction by vascular endothelial growth factor receptors","volume":"2","author":"Koch","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2943","DOI":"10.1200\/JCO.2002.12.116","article-title":"Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918","volume":"20","author":"Kruijtzer","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"6887","DOI":"10.1007\/s00018-021-03901-y","article-title":"Multidrug efflux transporter ABCG2: expression and regulation","volume":"78","author":"Kukal","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"607275","DOI":"10.3389\/fcell.2020.607275","article-title":"Establishment and characterization of a topotecan resistant non-small cell lung cancer NCI-H460\/TPT10 cell line","volume":"8","author":"Lei","year":"","journal-title":"Front. Cell Dev. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/mco2.106","article-title":"Overcoming multidrug resistance by knockout of ABCB1 gene using CRISPR\/Cas9 system in SW620\/Ad300 colorectal cancer cells","volume":"2","author":"Lei","year":"","journal-title":"MedComm"},{"key":"B25","doi-asserted-by":"publisher","first-page":"216181","DOI":"10.1016\/j.canlet.2023.216181","article-title":"A multi-functional nano-system combining PI3K-110\u03b1\/\u03b2 inhibitor overcomes P-glycoprotein mediated MDR and improves anti-cancer efficiency","volume":"563","author":"Lin","year":"2023","journal-title":"Cancer Lett."},{"key":"B26","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1152\/physiol.00046.2006","article-title":"Structure and function of ABC transporters","volume":"22","author":"Linton","year":"2007","journal-title":"Physiol. (Bethesda)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.3390\/cancers6031441","article-title":"The role of PI3K\/Akt\/mTOR signaling in gastric carcinoma","volume":"6","author":"Matsuoka","year":"2014","journal-title":"Cancers (Basel)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"7981","DOI":"10.1158\/0008-5472.CAN-10-0111","article-title":"Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-Binding cassette transporters","volume":"70","author":"Mi","year":"2010","journal-title":"Cancer Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1634\/stemcells.2006-0066","article-title":"Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies","volume":"24","author":"Mimeault","year":"2006","journal-title":"Stem Cells"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.3390\/toxins2061207","article-title":"Overcoming multidrug resistance in human cancer cells by natural compounds","volume":"2","author":"Nabekura","year":"2010","journal-title":"Toxins (Basel)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"949868","DOI":"10.3389\/fonc.2022.949868","article-title":"Anticancer effect of Indanone-based thiazolyl hydrazone derivative on p53 mutant colorectal cancer cell lines: an in vitro and in vivo study","volume":"12","author":"Narayanan","year":"2022","journal-title":"Front. Oncol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"53","DOI":"10.2147\/PGPM.S38295","article-title":"Human ABC transporter ABCG2\/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics","volume":"7","author":"Noguchi","year":"2014","journal-title":"Pharmgenomics Pers. Med."},{"key":"B33","first-page":"5850","article-title":"Reversal of a novel multidrug resistance mechanism in human Colon carcinoma cells by fumitremorgin C","volume":"58","author":"Rabindran","year":"1998","journal-title":"Cancer Res."},{"key":"B34","first-page":"47","article-title":"Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein","volume":"60","author":"Rabindran","year":"2000","journal-title":"Cancer Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1158\/0008-5472.can-03-3298","article-title":"Pheophorbide a is a specific probe for ABCG2 function and inhibition","volume":"64","author":"Robey","year":"2004","journal-title":"Cancer Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","article-title":"Revisiting the role of ABC transporters in multidrug-resistant cancer","volume":"18","author":"Robey","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"B37","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.semnephrol.2010.09.007","article-title":"Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker","volume":"30","author":"Robinson","year":"2010","journal-title":"Semin. Nephrol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"11012","DOI":"10.1158\/0008-5472.CAN-07-2686","article-title":"Erlotinib (tarceva, OSI-774) antagonizes ATP-Binding cassette subfamily B member 1 and ATP-Binding cassette subfamily G member 2-mediated drug resistance","volume":"67","author":"Shi","year":"2007","journal-title":"Cancer Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"8940","DOI":"10.1021\/bi060552f","article-title":"The calcium channel blockers, 1,4-dihydropyridines, are substrates of the multidrug resistance-linked ABC drug transporter, ABCG2","volume":"45","author":"Shukla","year":"2006","journal-title":"Biochemistry"},{"key":"B40","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1124\/dmd.108.024612","article-title":"Sunitinib (sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-Binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2","volume":"37","author":"Shukla","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"B41","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.drup.2012.01.005","article-title":"Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance","volume":"15","author":"Shukla","year":"2012","journal-title":"Drug Resist. Updat"},{"key":"B42","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nrd1984","article-title":"Targeting multidrug resistance in cancer","volume":"5","author":"Szak\u00e1cs","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"B43","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.cell.2010.01.045","article-title":"Lymphangiogenesis: molecular mechanisms and future promise","volume":"140","author":"Tammela","year":"2010","journal-title":"Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"101028","DOI":"10.1016\/j.drup.2023.101028","article-title":"Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor","volume":"73","author":"Teng","year":"2024","journal-title":"Drug Resist. Updat"},{"key":"B45","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.bcp.2009.04.002","article-title":"Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1\/Pgp and ABCG2\/BCRP\/MXR transporters","volume":"78","author":"Tiwari","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1111\/jebm.12434","article-title":"ATP-Bending cassette (ABC) transporters in cancer: a review of recent updates","volume":"14","author":"Wang","year":"2021","journal-title":"J. Evid. Based Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1606857","DOI":"10.3389\/fphar.2025.1606857","article-title":"Reversal of ABCG2-mediated drug resistance by tinodasertib (ETC-206)","volume":"16","author":"Yang","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.2174\/0115748928394153250731033624","article-title":"ABC transporter protein-mediated multidrug resistance in breast cancer and development of targeting strategies","volume":"20","author":"Yu","year":"2025","journal-title":"Recent Pat. Anticancer Drug Discov."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e90135","DOI":"10.1371\/journal.pone.0090135","article-title":"Risks of proteinuria associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a systematic review and meta-analysis","volume":"9","author":"Zhang","year":"2014","journal-title":"PLoS One"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.3389\/fphar.2018.01097","article-title":"Olmutinib (BI1482694\/HM61713), a novel epidermal growth factor receptor tyrosine kinase inhibitor, reverses ABCG2-Mediated multidrug resistance in cancer cells","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.canlet.2018.10.032","article-title":"Regorafenib antagonizes BCRP-Mediated multidrug resistance in Colon cancer","volume":"442","author":"Zhang","year":"2019","journal-title":"Cancer Lett."},{"key":"B52","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s12943-019-1112-1","article-title":"The PI3K subunits, P110\u03b1 and P110\u03b2 are potential targets for overcoming P-gp and BCRP-Mediated MDR in cancer","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol. Cancer"},{"key":"B53","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s12943-022-01524-w","article-title":"CDK6-PI3K signaling axis is an efficient target for attenuating ABCB1\/P-gp mediated multi-drug resistance (MDR) in cancer cells","volume":"21","author":"Zhang","year":"2022","journal-title":"Mol. Cancer"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.2174\/0115748928357067250512112852","article-title":"B-9-8, a novel harman dimer, reverses ABCG2-mediated chemotherapeutic drug resistance","volume":"21","author":"Zhao","year":"2025","journal-title":"Recent Pat. Anticancer Drug Discov."},{"key":"B55","doi-asserted-by":"publisher","first-page":"e5172","DOI":"10.1371\/journal.pone.0005172","article-title":"Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function","volume":"4","author":"Zheng","year":"2009","journal-title":"PLoS One"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1857174\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:34:54Z","timestamp":1781760894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1857174\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":55,"alternative-id":["10.3389\/fphar.2026.1857174"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1857174","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"article-number":"1857174"}}