Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids
Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids
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DOI：
10.3892/or.2015.4077
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发表时间：
2015-09-01
期刊：
影响因子：
4.2
通讯作者：
Duenas-Gonzalez, Alfonso
中科院分区：
文献类型：
--
作者：
Cervantes-Madrid, Diana;Duenas-Gonzalez, Alfonso
靶向癌细胞的代谢改变有很强的理由。其中研究最多的是较高的糖酵解速率，脂肪酸（FA）的氨解和从头合成。尽管这些途径的药理学抑制剂的可用性，没有同时针对它们进行临床前研究。在本研究中，它是确定是否糖酵解，脂肪酸，己糖激酶-2，转氨酶和脂肪酸合成酶的从头合成的三个关键酶，分别过表达相比，原代成纤维细胞。此外，我们表明，在临床相关浓度的氯尼达明，6-重氮-5-氧代-L-正亮氨酸和奥利司他，已知的抑制剂，所提到的酶，发挥细胞活力抑制作用。这三种酶的遗传下调也降低了细胞活力。当作为三联组合给药时，这三种药物具有高度协同作用。值得注意的是，三联组合的细胞毒性在原代成纤维细胞中较低，并且当施用至健康BALB/c小鼠中时耐受良好。结果表明，三重代谢靶向的可行性和潜在的临床应用，值得进一步研究通过使用重新定位的旧药物或更新，更有选择性的抑制剂。
There is a strong rationale for targeting the metabolic alterations of cancer cells. The most studied of these are the higher rates of glycolysis, glutaminolysis and de novo synthesis of fatty acids (FAs). Despite the availability of pharmacological inhibitors of these pathways, no preclinical studies targeting them simultaneously have been performed. In the present study it was determined whether three key enzymes for glycolysis, glutaminolysis and de novo synthesis of FAs, hexokinase-2, glutaminase and fatty acid synthase, respectively, were overexpressed as compared to primary fibroblasts. In addition, we showed that at clinically relevant concentrations lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat, known inhibitors of the mentioned enzymes, exerted a cell viability inhibitory effect. Genetic downregulation of the three enzymes also reduced cell viability. The three drugs were highly synergistic when administered as a triple combination. Of note, the cytotoxicity of the triple combination was low in primary fibroblasts and was well tolerated when administered into healthy BALB/c mice. The results suggest the feasibility and potential clinical utility of the triple metabolic targeting which merits to be further studied by using either repositioned old drugs or newer, more selective inhibitors.