Novel agents are desperately needed for improving the quality of life and 5-year survival to more than 30% for metastatic castrate-resistant
prostate cancer. Previously we showed that
Nexrutine, Phellodendron amurense bark extract, inhibits prostate
tumor growth in vitro and in vivo. Subsequently using biochemical fractionation we identified
butanol fraction contributes to the observed
biological activities. We report here that
palmatine, which is present in the
butanol fraction, selectively inhibits growth of
prostate cancer cells without significant effect on non-tumorigenic prostate epithelial cells. By screening
receptor tyrosine kinases in a
protein kinase array, we identified
ribosomal protein S6, a downstream target of
p70S6K and the Akt/mTOR signaling cascade as a potential target. We further show that
palmatine treatment is associated with decreased activation of NFκB and its downstream target gene FLIP. These events led to inhibition of invasion. Similar results were obtained using parent extract
Nexrutine (Nx) suggesting that
palmatine either in the purified form or as one of the components in Nx is a potent
cytotoxic agent with
tumor invasion inhibitory properties. Synergistic inhibition of rpS6/NFκB/FLIP axis with
palmatine may have therapeutic potential for the treatment of
prostate cancer and possibly other
malignancies with their constitutive activation. These data support a
biological link between rpS6/NFκB/FLIP in mediating
palmatine-induced inhibitory effects and warrants additional preclinical studies to test its therapeutic efficacy.