CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology , Chinese Academy of Sciences , Guangzhou 510301 , China.
Hubei Biopesticide Engineering Research Center , Hubei Academy of Agricultural Sciences , Wuhan 430064 , China.
J Med Chem. 2019 Aug 8;62(15):7058-7069. doi: 10.1021/acs.jmedchem.9b00598. Epub 2019 Jul 25.
Anti-renal cell carcinoma (RCC) agents with new mechanisms of action are urgently needed. Twenty-seven natural products of the piericidin class, including 17 new ones, are obtained from a marine-derived strain, and several of them show strong inhibitory activities against ACHN renal carcinoma cells. By exploring the mechanisms of two representative natural piericidin compounds, piericidin A (PA) and glucopiericidin A (GPA), peroxiredoxin 1 (PRDX1) is detected as a potential target by transcriptome data of PA-treated ACHN cells, as well as the paired RCC tumor versus adjacent nontumor tissues. PA and GPA induce cell apoptosis through reducing the reactive oxygen species level caused by upregulated PRDX1 mRNA and protein level subsequently and exhibit potent antitumor efficacy in nude mice bearing ACHN xenografts, with increasing PRDX1 expression in tumor. The interaction between PA/GPA and PRDX1 was supported by the docking analysis and surface plasmon resonance. Moreover, the translocation of PRDX1 into the nucleus forced by PA/GPA is proposed to be a key factor for the anti-RCC procedure. Piericidins provide a novel scaffold for further development of potent anti-RCC agents, and the new action mechanism of these agents targeting PRDX1 may improve upon the limitations of existing targeted drugs for the treatment of renal cancer.
迫切需要具有新作用机制的抗肾细胞癌 (RCC) 药物。从海洋来源的 菌株中获得了 27 种属于 Piericidin 类的天然产物，其中包括 17 种新化合物，它们中的几种对 ACHN 肾癌细胞具有很强的抑制活性。通过探索两种代表性天然 Piericidin 化合物（Piericidin A (PA) 和 Glucopiericidin A (GPA)）的作用机制，转录组数据分析表明，PA 处理的 ACHN 细胞以及配对的 RCC 肿瘤与相邻非肿瘤组织中，过氧化物还原酶 1 (PRDX1) 是一个潜在的靶点。PA 和 GPA 通过降低随后上调的 PRDX1 mRNA 和蛋白水平引起的活性氧水平诱导细胞凋亡，并在荷有 ACHN 异种移植物的裸鼠中表现出很强的抗肿瘤功效，肿瘤中 PRDX1 的表达增加。PA/GPA 与 PRDX1 之间的相互作用得到了对接分析和表面等离子体共振的支持。此外，PA/GPA 迫使 PRDX1 易位到细胞核被认为是抗 RCC 过程的一个关键因素。Piericidins 为进一步开发有效的抗 RCC 药物提供了一个新的支架，这些以 PRDX1 为靶点的药物的新作用机制可能改善现有针对肾癌治疗的靶向药物的局限性。
