ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression.
ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression.
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DOI：
10.1111/cts.12366
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Baker SD
中科院分区：
文献类型：
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作者：
Drenberg CD;Hu S;Li L;Buelow DR;Orwick SJ;Gibson AA;Schuetz JD;Sparreboom A;Baker SD
对阿糖胞苷的耐药性仍然是治疗急性髓细胞白血病（AML）的主要挑战。基于之前暗示ABCC 4/MRP 4参与核苷转运的研究，我们假设阿糖胞苷对ABCC 4介导的外排敏感，从而降低其针对AML母细胞的细胞毒性反应。发现在表达ABCC 4的囊泡中促进阿糖胞苷及其单磷酸代谢物的摄取，并且通过人ABCC 4或小鼠Abcc 4的过表达显著损害细胞内滞留（P < 0.05）。ABCC 4在AML原代母细胞和细胞系中高度表达，并且在ABCC 4抑制剂MK 571或索拉非尼存在下以及在ABCC 4 siRNA后，阿糖胞苷在细胞中的细胞毒性增加。在Abcc 4缺失小鼠中，阿糖胞苷诱导的血液学毒性增强，体外集落形成试验显示Abcc 4缺陷使髓系祖细胞对阿糖胞苷敏感。总的来说，这些研究表明ABCC 4在白血病和宿主骨髓细胞中对阿糖胞苷介导的损伤起保护作用。
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.