Sato Hiromi
Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University.
Yakugaku Zasshi. 2020;140(8):963-968. doi: 10.1248/yakushi.20-00012-1.
Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.
代谢组分析是一种从细胞持续产生和变化的代谢物来研究细胞特征的方法。我们对786-O肾细胞癌（RCC）细胞对组蛋白去乙酰化酶（HDAC）抑制剂的反应进行了代谢组分析，HDAC抑制剂有望提高抗癌药物敏感性，并将该反应与耐药细胞的反应进行比较。曲古抑菌素A（TSA）作为一种HDAC抑制剂，提高了786-O细胞对舒尼替尼的敏感性。此外，细胞的三羧酸循环和核苷酸代谢得到促进。乙酰化p53（活性形式）和早期凋亡细胞增加的结果表明，其机制涉及线粒体代谢和功能的增强。此外，将已建立的舒尼替尼耐药RCC细胞暴露于舒尼替尼和TSA的组合中，导致显著的生长抑制。主成分分析显示，亲代细胞和耐药细胞明显不同，但它们约一半的波动由相同的途径解释。总之，提示TSA通过触发能量代谢中的细胞内代谢组变化降低了舒尼替尼耐药性。这是首次认识到TSA作为HDAC抑制剂的作用机制。
