{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:10:39Z","timestamp":1788297039281,"version":"build-2803163510"},"reference-count":83,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan","award":["MOST-111-2320-B-182-018"],"award-info":[{"award-number":["MOST-111-2320-B-182-018"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST-110-2113-M-029-006"],"award-info":[{"award-number":["MOST-110-2113-M-029-006"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 109-2320-B-182-009-MY3"],"award-info":[{"award-number":["MOST 109-2320-B-182-009-MY3"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["MOST 111-2622-B-182-001"],"award-info":[{"award-number":["MOST 111-2622-B-182-001"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["109-2314-B-182A-097-MY3"],"award-info":[{"award-number":["109-2314-B-182A-097-MY3"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["CMRPD1M0581"],"award-info":[{"award-number":["CMRPD1M0581"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["BMRPC17"],"award-info":[{"award-number":["BMRPC17"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["CLRPD1J0014"],"award-info":[{"award-number":["CLRPD1J0014"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["TCVGH-T1107807"],"award-info":[{"award-number":["TCVGH-T1107807"]}]},{"name":"Ministry of Science and Technology, Taiwan","award":["010030"],"award-info":[{"award-number":["010030"]}]},{"name":"Chang Gung Memorial Hospital","award":["MOST-111-2320-B-182-018"],"award-info":[{"award-number":["MOST-111-2320-B-182-018"]}]},{"name":"Chang Gung Memorial Hospital","award":["MOST-110-2113-M-029-006"],"award-info":[{"award-number":["MOST-110-2113-M-029-006"]}]},{"name":"Chang Gung Memorial Hospital","award":["MOST 109-2320-B-182-009-MY3"],"award-info":[{"award-number":["MOST 109-2320-B-182-009-MY3"]}]},{"name":"Chang Gung Memorial Hospital","award":["MOST 111-2622-B-182-001"],"award-info":[{"award-number":["MOST 111-2622-B-182-001"]}]},{"name":"Chang Gung Memorial Hospital","award":["109-2314-B-182A-097-MY3"],"award-info":[{"award-number":["109-2314-B-182A-097-MY3"]}]},{"name":"Chang Gung Memorial Hospital","award":["CMRPD1M0581"],"award-info":[{"award-number":["CMRPD1M0581"]}]},{"name":"Chang Gung Memorial Hospital","award":["BMRPC17"],"award-info":[{"award-number":["BMRPC17"]}]},{"name":"Chang Gung Memorial Hospital","award":["CLRPD1J0014"],"award-info":[{"award-number":["CLRPD1J0014"]}]},{"name":"Chang Gung Memorial Hospital","award":["TCVGH-T1107807"],"award-info":[{"award-number":["TCVGH-T1107807"]}]},{"name":"Chang Gung Memorial Hospital","award":["010030"],"award-info":[{"award-number":["010030"]}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["MOST-111-2320-B-182-018"],"award-info":[{"award-number":["MOST-111-2320-B-182-018"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["MOST-110-2113-M-029-006"],"award-info":[{"award-number":["MOST-110-2113-M-029-006"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["MOST 109-2320-B-182-009-MY3"],"award-info":[{"award-number":["MOST 109-2320-B-182-009-MY3"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["MOST 111-2622-B-182-001"],"award-info":[{"award-number":["MOST 111-2622-B-182-001"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["109-2314-B-182A-097-MY3"],"award-info":[{"award-number":["109-2314-B-182A-097-MY3"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["CMRPD1M0581"],"award-info":[{"award-number":["CMRPD1M0581"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["BMRPC17"],"award-info":[{"award-number":["BMRPC17"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["CLRPD1J0014"],"award-info":[{"award-number":["CLRPD1J0014"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["TCVGH-T1107807"],"award-info":[{"award-number":["TCVGH-T1107807"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["010030"],"award-info":[{"award-number":["010030"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health","award":["MOST-111-2320-B-182-018"],"award-info":[{"award-number":["MOST-111-2320-B-182-018"]}]},{"name":"National Institutes of Health","award":["MOST-110-2113-M-029-006"],"award-info":[{"award-number":["MOST-110-2113-M-029-006"]}]},{"name":"National Institutes of Health","award":["MOST 109-2320-B-182-009-MY3"],"award-info":[{"award-number":["MOST 109-2320-B-182-009-MY3"]}]},{"name":"National Institutes of Health","award":["MOST 111-2622-B-182-001"],"award-info":[{"award-number":["MOST 111-2622-B-182-001"]}]},{"name":"National Institutes of Health","award":["109-2314-B-182A-097-MY3"],"award-info":[{"award-number":["109-2314-B-182A-097-MY3"]}]},{"name":"National Institutes of Health","award":["CMRPD1M0581"],"award-info":[{"award-number":["CMRPD1M0581"]}]},{"name":"National Institutes of Health","award":["BMRPC17"],"award-info":[{"award-number":["BMRPC17"]}]},{"name":"National Institutes of Health","award":["CLRPD1J0014"],"award-info":[{"award-number":["CLRPD1J0014"]}]},{"name":"National Institutes of Health","award":["TCVGH-T1107807"],"award-info":[{"award-number":["TCVGH-T1107807"]}]},{"name":"National Institutes of Health","award":["010030"],"award-info":[{"award-number":["010030"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Constitutive activation of the phosphoinositide-3-kinase (PI3K)\/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2\/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2\/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.<\/jats:p>","DOI":"10.3390\/cells12071056","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T01:37:02Z","timestamp":1680226622000},"page":"1056","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-3361","authenticated-orcid":false,"given":"Chung-Pu","family":"Wu","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Yu","family":"Hung","sequence":"additional","affiliation":[{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ju","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3920-2166","authenticated-orcid":false,"given":"Megumi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Yao","family":"Su","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Ho","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan"},{"name":"Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung 20401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4295-983X","authenticated-orcid":false,"given":"Jau-Song","family":"Yu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4027-0710","authenticated-orcid":false,"given":"Yu-Shan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Tunghai University, Taichung 40704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-4955","authenticated-orcid":false,"given":"Suresh V.","family":"Ambudkar","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"ref_1","first-page":"627","article-title":"Targeting the phosphoinositide 3-kinase pathway in cancer","volume":"8","author":"Liu","year":"2009","journal-title":"Nat. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.semcancer.2019.07.009","article-title":"PI3K\/Akt\/mTOR inhibitors in cancer: At the bench and bedside","volume":"59","author":"Alzahrani","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.stem.2009.01.007","article-title":"PTEN\/PI3K\/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells","volume":"4","author":"Bleau","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s00280-012-2043-3","article-title":"Overcoming acquired resistance to anticancer therapy: Focus on the PI3K\/AKT\/mTOR pathway","volume":"71","author":"Burris","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1080\/14737140.2017.1285702","article-title":"Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: Today and tomorrow","volume":"17","author":"Greenwell","year":"2017","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"105579","DOI":"10.1016\/j.phrs.2021.105579","article-title":"Properties of FDA-approved small molecule phosphatidylinositol 3-kinase inhibitors prescribed for the treatment of malignancies","volume":"168","author":"Roskoski","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114971","DOI":"10.1016\/j.ejmech.2022.114971","article-title":"Recent advances in PI3K\/PKB\/mTOR inhibitors as new anticancer agents","volume":"246","author":"Occhiuzzi","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"863","DOI":"10.3892\/or.2013.2499","article-title":"A novel imidazopyridine PI3K inhibitor with anticancer activity in non-small cell lung cancer cells","volume":"30","author":"Lee","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.canlet.2012.08.020","article-title":"HS-173, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, has anti-tumor activity through promoting apoptosis and inhibiting angiogenesis","volume":"328","author":"Lee","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s00508-020-01729-3","article-title":"HS-173, a selective PI3K inhibitor, induces cell death in head and neck squamous cell carcinoma cell lines","volume":"133","author":"Foki","year":"2021","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"105961","DOI":"10.1016\/j.ejps.2021.105961","article-title":"The inhibitors of KDM4 and KDM6 histone lysine demethylases enhance the anti-growth effects of erlotinib and HS-173 in head and neck cancer cells","volume":"166","author":"Kleszcz","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.canlet.2013.01.007","article-title":"Synergistic anticancer activity of HS-173, a novel PI3K inhibitor in combination with Sorafenib against pancreatic cancer cells","volume":"331","author":"Yun","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"44","DOI":"10.15761\/OHNS.1000111","article-title":"Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC","volume":"1","author":"Michmerhuizen","year":"2016","journal-title":"Otorhinolaryngol. Head Neck Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1124\/mol.118.115162","article-title":"Rationale for Using Irreversible Epidermal Growth Factor Receptor Inhibitors in Combination with Phosphatidylinositol 3-Kinase Inhibitors for Advanced Head and Neck Squamous Cell Carcinoma","volume":"95","author":"Michmerhuizen","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.1158\/0008-5472.CAN-08-4765","article-title":"PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers","volume":"69","author":"Wee","year":"2009","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s12935-021-01800-7","article-title":"ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384), a PI3K inhibitor in colorectal cancer cells","volume":"21","author":"Liu","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114137","DOI":"10.1016\/j.bcp.2020.114137","article-title":"Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K\/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines","volume":"180","author":"Wu","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/0005-2736(76)90160-7","article-title":"A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants","volume":"455","author":"Juliano","year":"1976","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15665","DOI":"10.1073\/pnas.95.26.15665","article-title":"A multidrug resistance transporter from human MCF-7 breast cancer cells","volume":"95","author":"Doyle","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nrc706","article-title":"Multidrug resistance in cancer: Role of ATP-dependent transporters","volume":"2","author":"Gottesman","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","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":"ref_22","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0378-4274(02)00497-6","article-title":"The role of multidrug transporters in drug availability, metabolism and toxicity","volume":"140","author":"Bodo","year":"2003","journal-title":"Toxicol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1152\/physrev.00037.2005","article-title":"Human multidrug resistance ABCB and ABCG transporters: Participation in a chemoimmunity defense system","volume":"86","author":"Sarkadi","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1158\/1078-0432.CCR-0937-3","article-title":"Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer","volume":"10","author":"Yoh","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_25","first-page":"287","article-title":"Role of ABC-cassette transporters (MDR1, MRP1, BCRP) in the development of primary and acquired multiple drug resistance in patients with early and metastatic breast cancer","volume":"35","author":"Kovalev","year":"2013","journal-title":"Exp. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1182\/blood.V96.1.365","article-title":"Expression of breast cancer resistance protein in blast cells from patients with acute leukemia","volume":"96","author":"Ross","year":"2000","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1038\/sj.leu.2402541","article-title":"BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia","volume":"16","author":"Steinbach","year":"2002","journal-title":"Leukemia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.leukres.2004.06.004","article-title":"BCRP mRNA expression v. clinical outcome in 40 adult AML patients","volume":"29","author":"Uggla","year":"2005","journal-title":"Leuk. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1080\/10428190600881421","article-title":"MDR-1, but not MDR-3 gene expression, is associated with unmutated IgVH genes and poor prognosis chromosomal aberrations in chronic lymphocytic leukemia","volume":"47","author":"Matthews","year":"2006","journal-title":"Leuk. Lymphoma"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1182\/blood-2005-10-009084","article-title":"ABCG2 expression, function, and promoter methylation in human multiple myeloma","volume":"108","author":"Turner","year":"2006","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1200\/JCO.2010.32.4962","article-title":"Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: Evidence for lenalidomide-CCI-779 interaction via P-glycoprotein","volume":"29","author":"Hofmeister","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1182\/blood-2005-10-4020","article-title":"Complex interaction of BCRP\/ABCG2 and imatinib in BCR-ABL-expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib-induced reduction of BCRP expression","volume":"108","author":"Nakanishi","year":"2006","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1111\/j.1476-5381.2009.00383.x","article-title":"Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: Implications for altered anti-cancer effects and pharmacological properties","volume":"158","author":"Hegedus","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.bcp.2012.11.003","article-title":"Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells","volume":"85","author":"Wu","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.bcp.2013.08.004","article-title":"Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1","volume":"86","author":"Wu","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1021\/mp500492r","article-title":"Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1","volume":"11","author":"Wu","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1021\/acs.molpharmaceut.5b00312","article-title":"Human ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1","volume":"12","author":"Wu","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wu, C.P., Hung, C.Y., Murakami, M., Wu, Y.S., Lin, C.L., Huang, Y.H., Hung, T.H., Yu, J.S., and Ambudkar, S.V. (2022). P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhiitor Ensartinib in Cancer Cells. Cancers, 14.","DOI":"10.3390\/cancers14092341"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.bcp.2018.07.018","article-title":"Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines","volume":"155","author":"Wu","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Wu, C.P., Hung, C.Y., Lusvarghi, S., Chang, Y.F., Hsiao, S.H., Huang, Y.H., Hung, T.H., Yu, J.S., and Ambudkar, S.V. (2021). Overexpression of Human ABCB1 and ABCG2 Reduces the Susceptibility of Cancer Cells to the Histone Deacetylase 6-Specific Inhibitor Citarinostat. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052592"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1021\/acs.molpharmaceut.5b00687","article-title":"Human ATP-Binding Cassette Transporter ABCG2 Confers Resistance to CUDC-907, a Dual Inhibitor of Histone Deacetylase and Phosphatidylinositol 3-Kinase","volume":"13","author":"Wu","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/978-1-60761-416-6_4","article-title":"Mechanisms of multidrug resistance in cancer","volume":"596","author":"Gillet","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.bcp.2007.12.001","article-title":"Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1((R))","volume":"75","author":"Robey","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1038\/sj.bjc.6601370","article-title":"Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity","volume":"89","author":"Robey","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1126\/science.3457471","article-title":"Human multidrug-resistant cell lines: Increased mdr1 expression can precede gene amplification","volume":"232","author":"Shen","year":"1986","journal-title":"Science"},{"key":"ref_46","first-page":"6635","article-title":"Acquired mutations in the MXR\/BCRP\/ABCP gene alter substrate specificity in MXR\/BCRP\/ABCP-overexpressing cells","volume":"61","author":"Honjo","year":"2001","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1177\/1087057105284576","article-title":"A high-throughput cell-based assay for inhibitors of ABCG2 activity","volume":"11","author":"Henrich","year":"2006","journal-title":"J. Biomol. Screen"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1158\/1535-7163.MCT-07-2005","article-title":"Evidence for dual mode of action of a thiosemicarbazone, NSC73306: A potent substrate of the multidrug resistance linked ABCG2 transporter","volume":"6","author":"Wu","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_49","first-page":"8634","article-title":"Karyotypic complexity of the NCI-60 drug-screening panel","volume":"63","author":"Roschke","year":"2003","journal-title":"Cancer Res."},{"key":"ref_50","first-page":"8","article-title":"Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: Demonstration of homology to ABC transport genes","volume":"59","author":"Miyake","year":"1999","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1248\/bpb.19.1518","article-title":"A combined assay of cell viability and in vitro cytotoxicity with a highly water-soluble tetrazolium salt, neutral red and crystal violet","volume":"19","author":"Ishiyama","year":"1996","journal-title":"Biol. Pharm. Bull."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/0005-2736(94)90190-2","article-title":"Calcein accumulation as a fluorometric functional assay of the multidrug transporter","volume":"1191","author":"Hollo","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","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":"ref_54","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s002320001020","article-title":"Functional characterization of glycosylation-deficient human P-glycoprotein using a vaccinia virus expression system","volume":"173","author":"Gribar","year":"2000","journal-title":"J. Membr. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/ni871","article-title":"Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells","volume":"4","author":"Anderson","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1021\/acs.molpharmaceut.6b00249","article-title":"Osimertinib (AZD9291) Attenuates the Function of Multidrug Resistance-Linked ATP-Binding Cassette Transporter ABCB1 in Vitro","volume":"13","author":"Hsiao","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/S0076-6879(98)92039-0","article-title":"Drug-stimulatable ATPase activity in crude membranes of human MDR1-transfected mammalian cells","volume":"292","author":"Ambudkar","year":"1998","journal-title":"Methods Enzymol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1126\/science.aav7102","article-title":"Structural insight into substrate and inhibitor discrimination by human P-glycoprotein","volume":"363","author":"Alam","year":"2019","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1038\/s41467-020-16155-2","article-title":"ABCG2 transports anticancer drugs via a closed-to-open switch","volume":"11","author":"Orlando","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"113663","DOI":"10.1016\/j.biopha.2022.113663","article-title":"The WD repeat-containing protein 5 (WDR5) antagonist WDR5-0103 restores the efficacy of cytotoxic drugs in multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2","volume":"154","author":"Wu","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"621","DOI":"10.2174\/138945011795378540","article-title":"Improving cancer chemotherapy with modulators of ABC drug transporters","volume":"12","author":"Shukla","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.ejmech.2017.07.062","article-title":"Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents","volume":"142","author":"Beretta","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1126\/science.6137059","article-title":"Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines","volume":"221","author":"Kartner","year":"1983","journal-title":"Science"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1124\/jpet.103.063149","article-title":"ABCG2 mediates differential resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and homocamptothecins","volume":"310","author":"Bates","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_65","first-page":"4559","article-title":"Overexpression of the BCRP\/MXR\/ABCP gene in a topotecan-selected ovarian tumor cell line","volume":"59","author":"Maliepaard","year":"1999","journal-title":"Cancer Res."},{"key":"ref_66","first-page":"145","article-title":"Overexpression of the ATP-binding Cassette Half-Transporter, ABCG2 (MXR\/BCRP\/ABCP1), in Flavopiridol-resistant Human Breast Cancer Cells","volume":"7","author":"Robey","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev.pharmtox.39.1.361","article-title":"Biochemical, cellular, and pharmacological aspects of the multidrug transporter","volume":"39","author":"Ambudkar","year":"1999","journal-title":"Ann. Rev. Pharmacol. Toxicol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.canlet.2018.12.006","article-title":"HS-173 as a novel inducer of RIP3-dependent necroptosis in lung cancer","volume":"444","author":"Park","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"100082","DOI":"10.1016\/j.mtbio.2020.100082","article-title":"Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy","volume":"8","author":"Landry","year":"2020","journal-title":"Mater. Today Bio"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.3892\/ijo.2013.1905","article-title":"A novel PI3K inhibitor alleviates fibrotic responses in fibroblasts derived from Peyronie\u2019s plaques","volume":"42","author":"Jung","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1038\/srep03470","article-title":"HS-173, a novel PI3K inhibitor, attenuates the activation of hepatic stellate cells in liver fibrosis","volume":"3","author":"Son","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"78029","DOI":"10.18632\/oncotarget.12871","article-title":"HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer","volume":"7","author":"Rumman","year":"2016","journal-title":"Oncotarget"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"112893","DOI":"10.18632\/oncotarget.22850","article-title":"Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer","volume":"8","author":"Park","year":"2017","journal-title":"Oncotarget"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.canlet.2017.06.035","article-title":"Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery","volume":"403","author":"Kim","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_75","first-page":"1703","article-title":"The PI3K\/Akt inhibitor LY294002 reverses BCRP-mediated drug resistance without affecting BCRP translocation","volume":"27","author":"Imai","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ejphar.2017.09.001","article-title":"Dual effects of the PI3K inhibitor ZSTK474 on multidrug efflux pumps in resistant cancer cells","volume":"815","author":"Muthiah","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/aps.2016.121","article-title":"The PI3K\/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia","volume":"38","author":"Deng","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.lungcan.2012.07.005","article-title":"Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy","volume":"78","author":"Fischer","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"248","DOI":"10.4149\/neo_2012_032","article-title":"Perifosine downregulates MDR1 gene expression and reverses multidrug-resistant phenotype by inhibiting PI3K\/Akt\/NF-kappaB signaling pathway in a human breast cancer cell line","volume":"59","author":"Lin","year":"2012","journal-title":"Neoplasma"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"129556","DOI":"10.1016\/j.bbagen.2020.129556","article-title":"A dual PI3 kinase\/mTOR inhibitor BEZ235 reverses doxorubicin resistance in ABCB1 overexpressing ovarian and pancreatic cancer cell lines","volume":"1864","author":"Durrant","year":"2020","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"873649","DOI":"10.3389\/fonc.2022.873649","article-title":"DHW-221, a Dual PI3K\/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp\/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer","volume":"12","author":"Liu","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature22345","article-title":"Structure of the human multidrug transporter ABCG2","volume":"546","author":"Taylor","year":"2017","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2174\/1567201043480036","article-title":"The role of ABC transporters in drug resistance, metabolism and toxicity","volume":"1","author":"Glavinas","year":"2004","journal-title":"Curr. Drug Deliv."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/7\/1056\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:07:42Z","timestamp":1760123262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/7\/1056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":83,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cells12071056"],"URL":"https:\/\/doi.org\/10.3390\/cells12071056","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]}}}