{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:30:19Z","timestamp":1780965019618,"version":"3.54.1"},"reference-count":34,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and objectives: The multidrug resistance protein 4 (MRP4) is a member of the ABC transporter, which has been extensively related to many types of cancer including leukemia. MRP4 overexpression and activity over the efflux of some chemotherapeutic drugs are the main causes of chemoresistance. 6-mercaptopurine (6-MP) is a chemotherapeutic drug widely used in the consolidation and maintenance phases of leukemia treatment. However, 6-MP is a substrate of MRP4, which decreases its chemotherapeutic efficacy. Current research is focused on the development of MRP4 inhibitors to combat chemoresistance by allowing the accumulation of the drug substrates inside the cells. To date, the only specific MRP4 inhibitor that has been developed is ceefourin-1, which has been reported to inhibit MRP4 in many cancer cells and which makes it an excellent candidate to enhance the activity of 6-MP in a combined treatment in vitro of leukemic cells. Materials and methods: in the present work, we determined the enhancing activity of ceefourin-1 on the antiproliferative and apoptotic effect of 6-MP in leukemic Jurkat cells by trypan blue assay and flow cytometry. Besides, we determined the 6-MP and ceefourin-1 binding sites into MRP4 by molecular docking and molecular dynamics. Results: ceefourin-1 enhanced the apoptotic activity of 6-MP in Jurkat cells, while in CRL-1991 cells both antiproliferative and apoptotic effect were significantly lower. Ceefourin-1 additively cooperates with 6-MP to induce apoptosis in leukemic cells, but normal lymphoblast CRl-1991 showed resistance to both drugs. Conclusion: ceefourin-1 and 6-MP cooperates to trigger apoptosis in leukemic Jurkat cells, but the full mechanism needs to be elucidated in further works. In addition, our perspective is to test the cooperation between ceefourin-1 and 6-MP in samples from patients and healthy donnors.<\/jats:p>","DOI":"10.3390\/medicina58060695","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:14:14Z","timestamp":1653437654000},"page":"695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Specific MRP4 Inhibitor Ceefourin-1 Enhances Apoptosis Induced by 6-Mercaptopurine in Jurkat Leukemic Cells, but Not in Normal Lymphoblast Cell Line CRL-1991"],"prefix":"10.3390","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3654-024X","authenticated-orcid":false,"given":"Edgardo","family":"Becerra","sequence":"first","affiliation":[{"name":"Posgrado en Ciencias Qu\u00edmico Biol\u00f3gicas, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Cerro de las Campanas S\/N, Quer\u00e9taro 76010, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6266-3457","authenticated-orcid":false,"given":"Laura","family":"Berumen","sequence":"additional","affiliation":[{"name":"Posgrado en Ciencias Qu\u00edmico Biol\u00f3gicas, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Cerro de las Campanas S\/N, Quer\u00e9taro 76010, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7239-2435","authenticated-orcid":false,"given":"Valeria","family":"Soto-Ontiveros","sequence":"additional","affiliation":[{"name":"Facultad de Qui\u0301mica, Universidad Auto\u0301noma de Quere\u0301taro, Centro Universitario, Quere\u0301taro 76010, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Garc\u00eda-Alcocer","sequence":"additional","affiliation":[{"name":"Posgrado en Ciencias Qu\u00edmico Biol\u00f3gicas, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Cerro de las Campanas S\/N, Quer\u00e9taro 76010, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"116540","DOI":"10.1016\/j.lfs.2019.06.015","article-title":"Multidrug resistance-associated protein 4 in pharmacology: Overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics","volume":"231","author":"Berthier","year":"2019","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.leukres.2007.09.015","article-title":"Up-regulation of MRP4 and down-regulation of influx transporters in human leukemic cells with acquired resistance to 6-mercaptopurine","volume":"32","author":"Peng","year":"2008","journal-title":"Leuk. 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