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Based on previous studies implicating ABCC4\/MRP4 in the transport of nucleosides, we hypothesized that cytarabine is sensitive to ABCC4\u2010mediated efflux, thereby decreasing its cytotoxic response against AML blasts. The uptake of cytarabine and its monophosphate metabolite was found to be facilitated in ABCC4\u2010expressing vesicles and intracellular retention was significantly impaired by overexpression of human ABCC4 or mouse Abcc4 (<jats:italic>P<\/jats:italic> &lt; 0.05). ABCC4 was expressed highly in AML primary blasts and cell lines, and cytotoxicity of cytarabine in cells was increased in the presence of the ABCC4 inhibitors MK571 or sorafenib, as well as after ABCC4 siRNA. In Abcc4\u2010null mice, cytarabine\u2010induced hematological toxicity was enhanced and <jats:italic>ex vivo<\/jats:italic> colony\u2010forming assays showed that Abcc4\u2010deficiency sensitized myeloid progenitors to cytarabine. Collectively, these studies demonstrate that ABCC4 plays a protective role against cytarabine\u2010mediated insults in leukemic and host myeloid cells.<\/jats:p>","DOI":"10.1111\/cts.12366","type":"journal-article","created":{"date-parts":[[2016,2,4]],"date-time":"2016-02-04T05:38:42Z","timestamp":1454564322000},"page":"51-59","source":"Crossref","is-referenced-by-count":30,"title":["ABCC4 Is a Determinant of Cytarabine\u2010Induced Cytotoxicity and Myelosuppression"],"prefix":"10.1111","volume":"9","author":[{"given":"CD","family":"Drenberg","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DR","family":"Buelow","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SJ","family":"Orwick","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AA","family":"Gibson","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JD","family":"Schuetz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Sparreboom","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SD","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,4]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0054-9"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2007.09.015"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11434-011-4840-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.166868"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24207"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.17.7612-7621.2004"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2008.01.006"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/12487"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djr107"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-07-2218"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203262200"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-03-1154"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-0048"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.05.022"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-4913"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6790"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2007.03.034"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1420"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-3623"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-1340"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428190290016773"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2004.05319.x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.10.3763"},{"key":"e_1_2_8_24_1","first-page":"1083","article-title":"Response to chemotherapy and expression of the genes encoding the multidrug resistance\u2010associated proteins MRP2, MRP3, MRP4, MRP5, and SMRP in childhood acute myeloid leukemia","volume":"9","author":"Steinbach D.","year":"2003","journal-title":"Clin. 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