title: ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression.
abstract: Resistance to cytarabine remains a major challenge in the treatment of acute myeloid leukemia (AML). Based on previous studies implicating ABCC4/MRP4 in the transport of nucleosides, we hypothesized that cytarabine is sensitive to ABCC4-mediated efflux, thereby decreasing its cytotoxic response against AML blasts. The uptake of cytarabine and its monophosphate metabolite was found to be facilitated in ABCC4-expressing vesicles and intracellular retention was significantly impaired by overexpression of human ABCC4 or mouse Abcc4 (P < 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-null mice, cytarabine-induced hematological toxicity was enhanced and ex vivo colony-forming assays showed that Abcc4-deficiency sensitized myeloid progenitors to cytarabine. Collectively, these studies demonstrate that ABCC4 plays a protective role against cytarabine-mediated insults in leukemic and host myeloid cells.
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: C D
authors: CD
authors: Drenberg
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: S
authors: S
authors: Hu
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: L
authors: L
authors: Li
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: D R
authors: DR
authors: Buelow
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: S J
authors: SJ
authors: Orwick
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: A A
authors: AA
authors: Gibson
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: J D
authors: JD
authors: Schuetz
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: A
authors: A
authors: Sparreboom
authors: Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, USA.
authors: S D
authors: SD
authors: Baker
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002675:Child, Preschool; D003561:Cytarabine / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D003561:Cytarabine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human; C489540:Abcc4 protein, mouse