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 Streptomyces 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.
Journal of medicinal chemistry. 2019 Jul 25 [Epub ahead of print]
Xuefeng Zhou, Zhi Liang, Kunlong Li, Wei Fang, Yuanxin Tian, Xiaowei Luo, Yulian Chen, Zhikun Zhan, Tao Zhang, Shengrong Liao, Shuwen Liu, Yonghong Liu, William Fenical, Lan Tang
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., Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California at San Diego , La Jolla , California 92093 , United States.