Inhibitors of GLUT/SLC2A Enhance the Action of BCNU and Temozolomide against High-Grade Gliomas.
Inhibitors of GLUT/SLC2A Enhance the Action of BCNU and Temozolomide against High-Grade Gliomas.
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DOI：
10.1016/j.neo.2017.02.009
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Magrassi L
中科院分区：
文献类型：
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作者：
Azzalin A;Nato G;Parmigiani E;Garello F;Buffo A;Magrassi L
葡萄糖跨胶质母细胞瘤膜的转运在维持高级别胶质瘤和胶质母细胞瘤典型的增强糖酵解方面起着至关重要的作用。我们测试了葡萄糖转运蛋白 GLUT/SLC2A 超家族的两种抑制剂茚地那韦 (IDV) 和利托那韦 (RTV) 以及 Na/葡萄糖逆向转运蛋白 2 型 (SGLT2/SLC5A2) 超家族的一种抑制剂根皮苷 (PHZ) 在降低人类和小鼠胶质母细胞瘤细胞的葡萄糖消耗和细胞增殖方面的能力。我们在体外发现，RTV 对至少三种不同的 GLUT/SLC2A 转运蛋白有活性，在降低葡萄糖消耗和乳酸产生以及抑制 U87MG 和 Hu197 人胶质母细胞瘤细胞系和人胶质母细胞瘤原代培养物的生长方面比 IDV（GLUT4/SLC2A4 的特异性抑制剂）更有效。 PHZ 对相同细胞没有活性。当细胞贴壁生长或作为 3D 多细胞肿瘤球体生长时，获得了类似的结果。 RTV 处理（而非 IDV 处理）诱导 AMP 激活蛋白激酶 (AMPKα) 磷酸化，与糖酵解活性和细胞生长的降低相平行。 IDV（而非 RTV）诱导 GLUT1/SLC2A1 的增加，其活性可以补偿 IDV 对 GLUT4/SLC2A4 的抑制。 RTV 和 IDV 很难通过血脑屏障，并且作为单一药物不太可能在体内达到足够的液体浓度来抑制胶质母细胞瘤的生长。 RTV 或 IDV 与 1,3-双(2-氯乙基)-1-亚硝基脲 (BCNU) 或 4-甲基-5-氧代-2,3,4,6,8-五氮杂双环[4.3.0]nona-2,7,9-三烯-9-甲酰胺 (TMZ) 关联的等效线图分析表明仅与 RTV 在抑制胶质母细胞瘤细胞方面具有协同作用。最后，我们在已建立的 GL261 肿瘤上体内测试了 RTV 和 BCNU 的组合。这种药物组合提高了总体生存率，并使 BCNU 的剂量减少了五倍。
Glucose transport across glioblastoma membranes plays a crucial role in maintaining the enhanced glycolysis typical of high-grade gliomas and glioblastoma. We tested the ability of two inhibitors of the glucose transporters GLUT/SLC2A superfamily, indinavir (IDV) and ritonavir (RTV), and of one inhibitor of the Na/glucose antiporter type 2 (SGLT2/SLC5A2) superfamily, phlorizin (PHZ), in decreasing glucose consumption and cell proliferation of human and murine glioblastoma cells. We found in vitro that RTV, active on at least three different GLUT/SLC2A transporters, was more effective than IDV, a specific inhibitor of GLUT4/SLC2A4, both in decreasing glucose consumption and lactate production and in inhibiting growth of U87MG and Hu197 human glioblastoma cell lines and primary cultures of human glioblastoma. PHZ was inactive on the same cells. Similar results were obtained when cells were grown in adherence or as 3D multicellular tumor spheroids. RTV treatment but not IDV treatment induced AMP-activated protein kinase (AMPKα) phosphorylation that paralleled the decrease in glycolytic activity and cell growth. IDV, but not RTV, induced an increase in GLUT1/SLC2A1 whose activity could compensate for the inhibition of GLUT4/SLC2A4 by IDV. RTV and IDV pass poorly the blood brain barrier and are unlikely to reach sufficient liquoral concentrations in vivo to inhibit glioblastoma growth as single agents. Isobologram analysis of the association of RTV or IDV and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide (TMZ) indicated synergy only with RTV on inhibition of glioblastoma cells. Finally, we tested in vivo the combination of RTV and BCNU on established GL261 tumors. This drug combination increased the overall survival and allowed a five-fold reduction in the dose of BCNU.