Medicinal herbs inhibit prostate cancer (PCa) via PI3 kinase and p21 mechanisms

Abstract

Our preliminary data showed that a combination of medicinal herbs is far superior in inhibiting PCa growth compared to individual herbs. We explored the molecular mechanisms responsible for these effects in vitro (22Rv1 PCa cells) and in vivo (using a CWR22 PCa cell xenograph model). Zyflamend®, a mixture containing extracts of 10 medicinal herbs, inhibited growth of 22Rv1 cells (individual herbs had no effect) by inhibiting PI3 kinase activity and downstream signaling, i.e, reductions in pAKT, SREBP‐1c, FAS, androgen receptor (AR), IGF‐1R and induction of p21and p27. Cell cycle inhibitor p21 is commonly lower in PCa, and Zyflamend® dramatically increased and stabilized p21 mRNA and protein through a p53‐independent mechanism. The p21 effects were confirmed with SiRNA experiments. Reductions in cell proliferation coincided with these molecular effects along with increases in apoptosis. This herbal combination (but not individual herbs) suppressed expression of Class I and II histone deacetylases (HDACs), suggesting epigenetic regulation of p21. In vivo, Zyflamend® enhanced tumor regression following androgen withdrawal by inhibiting HDACs, IGF‐1R, and AR expression, all critical in preventing PCa relapse. Our results suggest this herbal combination coordinately affects multiple signaling pathways to inhibit PCa tumor cell growth and promote cell death. (Supported by NewChapter, Brattleboro, VT).Grant Funding Source: NewChaper Inc.