Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells.
Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells.
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DOI：
10.3389/fphar.2018.01129
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发表时间：
2018
影响因子：
5.6
通讯作者：
Makinoshima H
中科院分区：
文献类型：
--
作者：
Sato Y;Matsuda S;Maruyama A;Nakayama J;Miyashita T;Udagawa H;Umemura S;Yanagihara K;Ochiai A;Tomita M;Soga T;Tsuchihara K;Makinoshima H
抗叶酸剂是一类有效治疗恶性胸膜间皮瘤（MPM）的药物。大多数抗叶酸剂抑制参与嘌呤和嘧啶合成的酶，如二氢叶酸还原酶（DHFR）、胸苷酸合成酶（TYMS）和甘氨酰胺核糖核苷酸甲酰转移酶（GART）。为了选择最合适的患者进行针对特定代谢途径的药物的有效治疗，需要更好的预测性代谢生物标志物。抗叶酸剂可以改变MPM细胞的整体代谢途径，但处理细胞的代谢谱尚未明确阐明。在这里，我们发现MPM细胞系可以根据其对培美曲塞治疗的敏感性或耐药性分为两组。我们发现，培美曲塞的敏感性可以逆转，DNA合成救援药物处理的细胞通过外源性添加核苷酸前体次黄嘌呤和胸苷（HT）。我们观察到耐药MPM细胞中培美塞汀靶向酶的表达定量低于培美塞汀敏感细胞中的表达。代谢组学分析表明，甘氨酸和胆碱，这是参与一碳代谢，改变药物治疗后，培美塞敏感，但不耐药的MPM细胞。HT的加入上调了培美曲塞敏感的MPM细胞中肌苷一磷酸（IMP）的浓度，表明核酸生物合成途径对于预测培美曲塞在MPM细胞中的疗效很重要。我们的数据提供了可能将治疗反应与代谢调节联系起来的证据，并指出了潜在的生物标志物，用于为MPM患者提供最有效的治疗方法。
Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM.
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影响因子：
--
作者：
Satoh T;Tatsuta T;Sugawara S;Hara A;Hosono M
通讯作者：
Hosono M
影响因子：
64.8
作者：
Palm W;Thompson CB
通讯作者：
Thompson CB
DOI：
10.1074/jbc.m114.575464
发表时间：
2014-07-25
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Makinoshima H;Takita M;Matsumoto S;Yagishita A;Owada S;Esumi H;Tsuchihara K
通讯作者：
Tsuchihara K
DOI：
10.1126/science.aad5214
发表时间：
2016-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kryukov GV;Wilson FH;Ruth JR;Paulk J;Tsherniak A;Marlow SE;Vazquez F;Weir BA;Fitzgerald ME;Tanaka M;Bielski CM;Scott JM;Dennis C;Cowley GS;Boehm JS;Root DE;Golub TR;Clish CB;Bradner JE;Hahn WC;Garraway LA
通讯作者：
Garraway LA
DOI：
10.1073/pnas.1706617114
发表时间：
2017-10-24
影响因子：
11.1
作者：
Ducker, Gregory S.;Ghergurovich, Jonathan M.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.