Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan; Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Eur J Pharmacol. 2019 Mar 15;847:143-157. doi: 10.1016/j.ejphar.2019.01.040. Epub 2019 Jan 26.
Although sunitinib is the first-line drug for progressive renal cell carcinoma (RCC), most patients experience its tolerance. One possible way of overcoming drug resistance is combination therapy. Epigenetic modifier is one of the candidate drug group. A recent evidence suggests that cell metabolism is regulated by epigenetic mechanisms. Epigenetic abnormalities lead to changes in metabolism and may contribute to drug resistance and progression of RCC. Consequently, we investigated whether trichostatin A (TSA), a potent histone-deacetylase (HDAC) inhibitor, alters sunitinib-induced cytotoxicity and metabolism in RCC cells at epigenetic regulatory concentrations. Combined metabolome and transcriptome analysis suggested that TSA impacts on energy productive metabolic pathways, such as those involving TCA cycle and nucleotide metabolism especially for increase of hyperphosphorylated form. Combination of sunitinib and TSA increased cell death with PARP cleavage, an early marker of mitochondrial apoptosis, whereas receptor tyrosine kinase signaling, which is the target of sunitinib, was not altered by TSA. Finally, the established sunitinib resistant-RCC cell (786-O Res) was also exposed to sunitinib and TSA combination, resulting in significant growth inhibition. In summary, it was suggested that TSA reduces sunitinib resistance by triggering intracellular metabolome shifts regarding energy metabolism, that is the first recognized mechanism as an HDAC inhibitor.
虽然舒尼替尼是治疗进展性肾细胞癌（RCC）的一线药物，但大多数患者对其耐受。克服耐药性的一种可能方法是联合治疗。表观遗传修饰剂是候选药物组之一。最近的证据表明，细胞代谢受表观遗传机制调控。表观遗传异常导致代谢改变，并可能导致 RCC 耐药性和进展。因此，我们研究了在表观遗传调节浓度下，组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素 A（TSA）是否会改变 RCC 细胞中舒尼替尼诱导的细胞毒性和代谢。联合代谢组学和转录组学分析表明，TSA 影响能量产生代谢途径，如三羧酸（TCA）循环和核苷酸代谢，特别是增加磷酸化形式。舒尼替尼和 TSA 的联合使用增加了细胞死亡，伴随着 PARP 切割，这是线粒体凋亡的早期标志物，而 TSA 并未改变舒尼替尼的受体酪氨酸激酶信号，该信号是舒尼替尼的靶点。最后，还将建立的舒尼替尼耐药-RCC 细胞（786-O Res）暴露于舒尼替尼和 TSA 联合治疗中，导致显著的生长抑制。总之，研究结果表明，TSA 通过触发与能量代谢有关的细胞内代谢组学变化来降低舒尼替尼的耐药性，这是作为 HDAC 抑制剂的第一个被认可的机制。
