Glutaminase activity determines cytotoxicity of L-asparaginases on most leukemia cell lines.
Glutaminase activity determines cytotoxicity of L-asparaginases on most leukemia cell lines.
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DOI：
10.1016/j.leukres.2015.04.008
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发表时间：
2015-07
影响因子：
2.7
通讯作者：
Mittelman, Steven D.
中科院分区：
文献类型：
--
作者：
Parmentier, Jean Hugues;Maggi, Maristella;Tarasco, Erika;Scotti, Claudia;Avramis, Vassilios I.;Mittelman, Steven D.
L-天冬酰胺酶 (ASNase) 是治疗急性淋巴细胞白血病 (ALL) 的一线化疗药物，通过使天冬酰胺和谷氨酰胺脱氨基发挥作用。为了评估谷氨酰胺酶活性的重要性，我们利用了最近开发的幽门螺杆菌 ASNase (dm HpA) 突变体，其中氨基酸替换为 M121C/T169M。突变体形式具有与野生型相同的天冬酰胺酶活性，但缺乏谷氨酰胺酶活性。将野生型和 dm HpA 与临床使用的大肠杆菌 (L-ASP) 和菊欧文氏菌 (ERWase) 的 ASNase 进行比较。所有异构体的天冬酰胺酶活性相似，而谷氨酰胺酶活性遵循以下顺序：ERWase > L-ASP > 野生型 HpA > dm HpA。在 11 种人类白血病细胞系和两种源自患者的 ALL 样本中测试了 ASNase 的细胞毒性功效。我们之前已经证明天冬酰胺依赖性的两种细胞系对天冬酰胺酶亚型同样敏感。其他九个品系和两个患者来源的样品对谷氨酰胺酶活性较高的异构体更敏感。总的来说，ERWase 是所有测试细胞系中最有效的 ASNase，而 dm HpA 的谷氨酰胺酶活性最低，效率最低。这些数据表明，单独的天冬酰胺酶活性可能不足以产生 ASNase 细胞毒性，并且谷氨酰胺酶活性可能是完全抗白血病功效所必需的。
L-Asparaginase (ASNase) is a front-line chemotherapy for acute lymphoblastic leukemia (ALL), which acts by deaminating asparagine and glutamine. To evaluate the importance of glutaminase activity, we exploited a recently developed mutant of Helicobacter pylori ASNase (dm HpA), with amino acid substitutions M121C/T169M. The mutant form has the same asparaginase activity as wild-type but lacks glutaminase activity. Wild-type and dm HpA were compared with the clinically used ASNases from E. coli (L-ASP) and Erwinia chrysanthemi (ERWase). Asparaginase activity was similar for all isoforms, while glutaminase activity followed the rank order: ERWase > L-ASP > wild-type HpA > dm HpA. Cytotoxic efficacy of ASNases was tested on 11 human leukemia cell lines and two patient-derived ALL samples. Two cell lines which we had previously shown to be asparagine-dependent were equally sensitive to the asparaginase isoforms. The other nine lines and the two patient-derived samples were more sensitive to isoforms with higher glutaminase activities. ERWase was overall the most effective ASNase on all cell lines tested whereas dm HpA, having the lowest glutaminase activity, was the least effective. These data demonstrate that asparaginase activity alone may not be sufficient for ASNase cytotoxicity, and that glutaminase activity may be required for full anti-leukemic efficacy.
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影响因子：
11.2
作者：
Ehsanipour EA;Sheng X;Behan JW;Wang X;Butturini A;Avramis VI;Mittelman SD
通讯作者：
Mittelman SD
影响因子：
4.1
作者：
Aslanian, AM;Kilberg, MS
通讯作者：
Kilberg, MS
影响因子：
20.3
作者：
Appel, Inge M.;den Boer, Monique L.;Pieters, Rob
通讯作者：
Pieters, Rob
影响因子：
5.7
作者：
Fei F;Stoddart S;Groffen J;Heisterkamp N
通讯作者：
Heisterkamp N
影响因子：
3.3
作者：
Abbatiello, Susan E.;Pan, Yuan-Xiang;Conrads, Thomas P.
通讯作者：
Conrads, Thomas P.