Polygonum multiflorum and its active ingredient Polygalacic acid suppress lethal prostate cancer growth by inducing cell cycle arrest

The incidence of prostate cancer ranks second among cancers in men and is one of the leading causes of cancer-related death worldwide. Contemporary therapy for metastatic prostate cancer employing reagents such as AR antagonists only provides a temporary response and rapidly acquires resistance and even eventually evolves into neuroendocrine prostate cancer (NEPC), which currently with no standard therapy. Polygonum multiflorum (PM), a medicinal plant that was an element of traditional medicine for centuries worldwide, was previously reported to suppress liver cancer cell growth, while its role and mechanisms in prostate cancer remain to be explored. In this study, we reported that PM significantly suppressed the growth of prostate cancer both in vitro and in vivo, and a low dose of PM significantly sensitized prostate cancer to AR antagonists. Mechanistically, RNA-seq revealed that PM induced G2/M-phase cell-cycle arrest by modulating cell cycle-related gene activation. Additionally, we demonstrated that polygalacic acid from PM and its structural analog ursolic acid and oleanolic acid suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDC2 phosphorylation, as knockdown of CDC25B with emerging CRISPR-Cas13 technology completely diminished polygalacic acid-induced cell growth inhibition. Our findings not only revealed the anti-tumor efficacy and mechanisms of PM but also demonstrated the potential benefits of combination treatment of prostate cancer with AR antagonists and traditional medicines, which dramatically increase the anti-tumor effect and may decelerate the resistance towards treatment with AR antagonists.