PURPOSE Glioblastoma is an aggressive central nervous system tumor with a 5-year survival rate of < 10%. The standard therapy for glioblastoma is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide. New approaches to treatment of glioblastoma, such as targeting metabolism, have been studied. The object of this study is to evaluate whether asparagine could be a new target for treatment of glioblastoma. METHODS We investigated a potential treatment for glioblastoma that targets the amino acid metabolism. U251, U87, and SF767 glioblastoma cells were treated with L-asparaginase and/or 6-diazo-5-oxo-L-norleucine (DON). L-asparaginase hydrolyzes asparagine into aspartate and depletes asparagine. L-asparaginase has been used for the treatment of acute lymphoblastic leukemia. DON is a glutamine analog that inhibits several glutamine-utilizing enzymes, including asparagine synthetase. RESULTS Cell viability was measured after 72 h of treatment. MTS assay showed that L-asparaginase suppressed the proliferation of U251, U87, and SF767 cells in a dose-dependent manner. DON also inhibited the proliferation of these cell lines in a dose-dependent manner. Combined treatment with these drugs had a synergistic antiproliferative effect in these cell lines. Exogenous asparagine rescued the effect of inhibition of proliferation by L-asparaginase and DON. The expression of asparagine synthetase mRNA was increased in cells treated with a combination of L-asparaginase and DON. This combined treatment also induced greater apoptosis and autophagy than did single-drug treatment. CONCLUSION The results suggest that the combination of L-asparaginase and DON could be a new therapeutic option for patients with glioblastoma.

中文翻译：

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L-天冬酰胺酶和6-重氮5-氧-L-正亮氨酸协同抑制胶质母细胞瘤细胞的生长。

目的胶质母细胞瘤是一种侵袭性中枢神经系统肿瘤，5年生存率<10％。胶质母细胞瘤的标准疗法是最大程度的安全切除，然后进行放射疗法和替莫唑胺化疗。已经研究了治疗胶质母细胞瘤的新方法，例如靶向代谢。这项研究的目的是评估天冬酰胺是否可以成为治疗胶质母细胞瘤的新靶标。方法我们研究了靶向氨基酸代谢的胶质母细胞瘤的潜在治疗方法。将U251，U87和SF767胶质母细胞瘤细胞用L-天冬酰胺酶和/或6-重氮-5-氧代-L-正亮氨酸（DON）处理。L-天冬酰胺酶将天冬酰胺水解为天冬氨酸并消耗天冬酰胺。L-天冬酰胺酶已被用于治疗急性淋巴细胞白血病。DON是一种谷氨酰胺类似物，可抑制几种利用谷氨酰胺的酶，包括天冬酰胺合成酶。结果治疗72小时后测量细胞活力。MTS分析表明，L-天冬酰胺酶以剂量依赖的方式抑制U251，U87和SF767细胞的增殖。DON也以剂量依赖性方式抑制这些细胞系的增殖。与这些药物联合治疗在这些细胞系中具有协同的抗增殖作用。外源天冬酰胺挽救了L-天冬酰胺酶和DON抑制增殖的作用。在用L-天冬酰胺酶和DON联合处理的细胞中，天冬酰胺合成酶mRNA的表达增加。与单药治疗相比，这种联合治疗还诱导了更大的凋亡和自噬。