Discovery of N-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents against Cancer Cells
Discovery of N-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents against Cancer Cells
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DOI：
10.1021/jm101007q
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发表时间：
2011-03-24
影响因子：
7.3
通讯作者：
Minutolo, Filippo
中科院分区：
文献类型：
--
作者：
Granchi, Carlotta;Roy, Sarabindu;Minutolo, Filippo
高度侵袭性的肿瘤细胞的特征在于被称为瓦尔堡效应的代谢开关，从“正常”氧化磷酸化到甚至低于正常氧化磷酸化的糖酵解增加。充分的氧化条件。这种对糖酵解的依赖性也赋予肿瘤缺氧区域中存在的细胞生长优势。参与糖酵解的关键酶之一，乳酸脱氢酶（LDH-A）的肌肉亚型，被转移性癌细胞过度表达，并与缺氧中肿瘤的活力有关。这种酶可能被认为是新抗癌药物的潜在靶点，因为它的抑制会切断癌症的能量和合成代谢供应，从而降低癌细胞的转移和侵袭潜力。我们已经发现了新的和有效的基于N-羟基吲哚的LDH-A抑制剂，其是异构体选择性的（相对于LDH-B），并且与底物（丙酮酸）和辅因子（NADH）竞争。这些化合物的抗增殖活性在一系列癌细胞系上得到证实，并且它们被证明在缺氧条件下特别有效。此外，NMR实验表明，这些化合物能够降低细胞内葡萄糖向乳酸的转化。
Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect, from "normal" oxidative phosphorylation to increased glycolysis even under. sufficiently oxygenated conditions. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. We have discovered new and efficient N-hydroxyindole-based inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH). The antiproliferative activity of these compounds was confirmed on a series of cancer cell lines, and they proved to be particularly effective under hypoxic conditions. Moreover, NMR experiments showed that these compounds are able to reduce the glucose-to-lactate conversion inside the cell.