ROLE OF HUMAN NUCLEOSIDE TRANSPORTERS IN THE UPTAKE AND CYTOTOXICITY OF AZACITIDINE AND DECITABINE
ROLE OF HUMAN NUCLEOSIDE TRANSPORTERS IN THE UPTAKE AND CYTOTOXICITY OF AZACITIDINE AND DECITABINE
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DOI：
10.1080/15257770.2011.652330
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发表时间：
2012-01-01
影响因子：
1.3
通讯作者：
Tong, Zeen
中科院分区：
文献类型：
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作者：
Damaraju, Vijaya L.;Mowles, Delores;Tong, Zeen
核苷类似物5-氮扎胞苷（阿扎胞苷）和5-氮扎-2'-脱氧胞苷（地西他滨）对急性髓系白血病和骨髓增生异常综合征有活性。细胞跨膜运输对这些高极性亲水性分子的摄取至关重要。我们评估了阿扎胞苷、地西他滨和吉西他滨在酿酒酵母细胞（hENT1/2、hCNT1/2/3）或非洲爪蟾卵母细胞（hENT3/4）中与人类核苷转运体（hNTs）相互作用的能力。三种药物对hCNT1/3的抑制作用均为强效（K值为3 ~ 26 mM），对hCNT2和hENT1/2的抑制作用较弱（K值为0.5 ~ 3.1 mM），对hENT3/4的抑制作用较差。[H-3]吉西他滨、[C-14]阿扎胞苷和[H-3]地西他滨在表达重组hNTs的爪蟾卵母细胞中的转运率存在显著差异。在没有或存在转运抑制剂的情况下，在表达hnt或缺乏hnt的培养人细胞系中评估了阿扎胞苷和地西他滨的细胞毒性。hNTs赋予的细胞毒性敏感性（IC50值，mu M）的等级为：阿扎胞苷的hCNT1 (0.1) > hENT1 (0.3) >> hCNT2 (8.3), hENT2(9.0)，而对地西他滨的hENT1 (0.3) > hCNT1 (0.8) >>> hENT2, hCNT2（>100）。在核苷转运抑制剂存在的情况下，观察到两种药物对细胞毒性的保护作用，从而表明hNTs在毒性表现中的重要性。综上所述，所有7种hNTs均转运阿扎胞苷，其中hCNT3转运率最高，而hENT1和hENT2转运适度，hCNT1和hCNT3转运地西他滨不佳。我们的研究结果首次表明，阿扎胞苷和地西他滨表现出不同的人类核苷转运谱，它们的细胞毒性依赖于hNTs的存在，hNTs可以作为临床反应的潜在生物标志物。
The nucleoside analogs 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine) are active against acute myeloid leukemia and myelodysplastic syndromes. Cellular transport across membranes is crucial for uptake of these highly polar hydrophilic molecules. We assessed the ability of azacitidine, decitabine, and, for comparison, gemcitabine, to interact with human nucleoside transporters (hNTs) in Saccharomyces cerevisiae cells (hENT1/2, hCNT1/2/3) or Xenopus laevis oocytes (hENT3/4). All three drugs inhibited hCNT1/3 potently (K; values, 3-26 AM), hENT1/2 and hCNT2 weakly (K; values, 0.5-3.1 mM), and hENT3/4 poorly if at all. Rates of transport of [H-3]gemcitabine, [C-14]azacitidine, and [H-3]decitabine observed in Xenopus oocytes expressing individual recombinant hNTs differed substantially. Cytotoxicity of azacitidine and decitabine was assessed in hNT-expressing or hNT-deficient cultured human cell lines in the absence or presence of transport inhibitors where available The rank order of cytotoxic sensitivities (IC50 values, mu M) conferred by hNTs were hCNT1 (0.1) > hENT1 (0.3) >> hCNT2 (8.3), hENT2 (9.0) for azacitidine and hENT1 (0.3) > hCNT1 (0.8) >>> hENT2, hCNT2 (>100) for decitabine. Protection against cytotoxicity was observed for both drugs in the presence of inhibitors of nucleoside transport, thus suggesting the importance of hNTs in manifestation of toxicity. In summary, all seven hNTs transported azacitidine, with hCNT3 showing the highest rates, whereas hENT1 and hENT2 showed modest transport and hCNT1 and hCNT3 poor transport of decitabine. Our results show for the first time that azacitidine and decitabine exhibit different human nucleoside transportability profiles and their cytotoxicities are dependent on the presence of hNTs, which could serve as potential biomarkers of clinical response.