Exploring the Natural Piericidins as Anti-Renal Cell Carcinoma Agents Targeting Peroxiredoxin 1

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.