发现人乳酸脱氢酶A（LDHA）抑制剂作为抗癌剂可抑制MG-63骨肉瘤细胞的增殖。
Discovery of human lactate dehydrogenase A (LDHA) inhibitors as anticancer agents to inhibit the proliferation of MG-63 osteosarcoma cells.
作者信息
Fang Aiping, Zhang Qi, Fan Haibo, Zhou Yaying, Yao Yuqin, Zhang Yue, Huang Xiaojun
机构信息
West China School of Public Health/No. 4 West China Teaching Hospital , Sichuan University , Chengdu , 610041 , Sichuan , P.R. China.
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy , West China Hospital , Sichuan University , Chengdu , 610041 , Sichuan , P.R. China.
出版信息
Medchemcomm. 2017 Jul 7;8(8):1720-1726. doi: 10.1039/c7md00222j. eCollection 2017 Aug 1.
Abstract
Human lactate dehydrogenase A (LDHA) has been identified as a potential therapeutic target in the area of cancer metabolism. Herein, we report the discovery of novel LDHA inhibitors through docking-based virtual screening and biological assays. The primary enzymatic assay suggested that compound targeted LDHA with an IC value of 0.33 μM. The cytotoxic assay demonstrated that compound reduced the growth of MG-63 cancer cells with an EC value of 3.35 μM. Finally, we found that compound induced the apoptosis of MG-63 cancer cells in a dose dependent manner, upregulated the oxygen consumption rate (OCR), and decreased the lactate formation and extracellular acidification rate (ECAR) in MG-63 cancer cells. Collectively, our data suggested that compound could be a promising lead for the development of potent LDHA inhibitors.
摘要
人乳酸脱氢酶A（LDHA）已被确定为癌症代谢领域的一个潜在治疗靶点。在此，我们报告通过基于对接的虚拟筛选和生物学测定发现新型LDHA抑制剂。初步酶活性测定表明，化合物对LDHA的靶向作用IC值为0.33μM。细胞毒性测定表明，化合物使MG-63癌细胞的生长减少，EC值为3.35μM。最后，我们发现化合物以剂量依赖性方式诱导MG-63癌细胞凋亡，上调氧消耗率（OCR），并降低MG-63癌细胞中的乳酸生成和细胞外酸化率（ECAR）。总体而言，我们的数据表明化合物可能是开发强效LDHA抑制剂的一个有前景的先导物。
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J Cancer Res Ther. 2016 Oct-Dec;12(4):1261-1265. doi: 10.4103/0973-1482.158035.
2
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