Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside
Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside
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DOI：
10.1158/1535-7163.mct-06-0001
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发表时间：
2006-09-01
影响因子：
5.7
通讯作者：
Swinnen, Johannes V.
中科院分区：
文献类型：
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作者：
Beckers, Annelies;Organe, Sophie;Swinnen, Johannes V.
由于核苷5-氨基咪唑-4-甲酰胺(AICA)能够模拟细胞的低能量状态，被认为是一种抗肿瘤药物，它可以阻断与恶性表型相关的主要能量消耗过程(脂质产生、DNA合成、细胞增殖、细胞迁移等)。AICA核苷抗肿瘤作用的关键是将其转化为ZMP，ZMP是一种AMP模拟物，在高浓度时可激活AMP激活的蛋白激酶(AMPK)。在这里，为了提高AICA核苷的疗效，我们用甲氨蝶呤(一种阻断ZMP代谢的抗代谢药物)对癌细胞进行预处理。甲氨蝶呤增加了AICA核苷诱导的ZMP的积聚，并导致作为AMPK空间内抑制剂的ATP水平下降。因此，甲氨蝶呤显著敏化AMPK被AICA核苷激活，并增强AICA核苷对肿瘤相关过程的抑制作用。由于联合治疗已经在单独使用时仅有微弱效果的化合物浓度下产生抗增殖作用，我们关于甲氨蝶呤和AICA核苷之间合作的研究结果为经典抗代谢化疗药物(如甲氨蝶呤)的应用和将能量传感机制用作癌症干预的靶点提供了新的机会。
Because of its ability to mimic a low energy status of the cell, the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside was proposed as an antineoplastic agent switching off major energy-consuming processes associated with the malignant phenotype (lipid production, DNA synthesis, cell proliferation, cell migration, etc.). Key to the antineoplastic action of AICA riboside is its conversion to ZMP, an AMP mimetic that at high concentrations activates the AMP-activated protein kinase (AMPK). Here, in an attempt to increase the efficacy of AICA riboside, we pretreated cancer cells with methotrexate, an antimetabolite blocking the metabolism of ZMP. Methotrexate enhanced the AICA riboside-induced accumulation of ZMP and led to a decrease in the levels of ATP, which functions as an intrasteric inhibitor of AMPK. Consequently, methotrexate markedly sensitized AMPK for activation by AICA riboside and potentiated the inhibitory effects of AICA riboside on tumor-associated processes. As cotreatment elicited antiproliferative effects already at concentrations of compounds that were only marginally effective when used alone, our findings on the cooperation between methotrexate and AICA riboside provide new opportunities both for the application of classic antimetabolic chemotherapeutics, such as methotrexate, and for the exploitation of the energy-sensing machinery as a target for cancer intervention.