{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:30:47Z","timestamp":1786595447328,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>ABCB1-mediated multidrug resistance (MDR) reduces the intracellular accumulation of anticancer drugs and limits chemotherapy efficacy. This study investigated whether umbralisib, a dual PI3K\u03b4\/CK1\u03f5 inhibitor, could reverse ABCB1-mediated MDR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The reversal effect of umbralisib was evaluated in ABCB1-overexpressing drug-selected and transfected cell models using MTT assays. Drug accumulation and efflux assays, ATPase analysis, molecular docking, Western blotting, immunofluorescence, apoptosis analysis, and 3D spheroid assays were performed to explore the underlying mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Umbralisib significantly sensitized ABCB1-overexpressing cells to paclitaxel, vincristine, and doxorubicin in a concentration-dependent manner, but did not markedly reverse ABCC1-, ABCG2-, or ABCC10-mediated MDR. Mechanistically, umbralisib increased intracellular [\n                      <jats:sup>3<\/jats:sup>\n                      H]-paclitaxel accumulation and inhibited its efflux without altering ABCB1 expression or membrane localization. ATPase analysis and molecular docking supported a potential interaction between umbralisib and the ABCB1 drug-binding cavity. Umbralisib also enhanced paclitaxel-induced apoptosis and restored chemosensitivity in 3D tumor spheroids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Umbralisib reverses ABCB1-mediated MDR mainly by inhibiting ABCB1 drug efflux rather than altering transporter expression or localization, providing mechanistic insight into the modulation of ABCB1-mediated chemoresistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1916572","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:24:47Z","timestamp":1786595087000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Umbralisib antagonizes multidrug resistance in ABCB1-overexpressing cancer cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Letao","family":"Bo","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanming","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["New York, NY, United States"]},{"name":"Affiliated Hospital of North China University of Science and Technology","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Zhong","sequence":"additional","affiliation":[{"name":"John L. Miller Great Neck North High School","place":["Great Neck, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meizi","family":"Tan","sequence":"additional","affiliation":[{"name":"Holy Trinity Diocesan High School","place":["Hicksville, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["New York, NY, United States"]},{"name":"Affiliated Hospital of North China University of Science and Technology","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harsh","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John N. 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