Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer
Technical Report,19 Jul 2012,18 Jul 2016
TULANE UNIV NEW ORLEANS LA NEW ORLEANS United States
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We have demonstrated that berberine BBR inhibits AR expression by down regulating its mRNA and inducing degradation of the AR protein. In contrast, BBR inhibition of AKT expression is mediated mainly by inducing protein degradation. By using a PTEN conditional knockout mouse model, we have demonstrated that BBR is effective in blocking the development and castration resistant progression of prostate cancer. These effects seem to be confined to the cancerous tissues, as normal prostates and other tissues are not affected by BBR. These results provide strong support for BBR as a chemoprevention agent targeting the development and progression of prostate cancer. Additionally, we have demonstrated that BBR inhibits the growth of castration-resistant xenografts driven by a constitutively active AR splice variant, and that BBR sensitizes AR-V-expressing tumors to enzalutamide treatment. These results suggest a role for BBR in the treatment of advanced prostate cancer, particularly in overcoming therapeutic resistance mediated by constitutively active AR splice variants. Finally, we have shown BBR blocks steroid genesis by inhibiting the activity of AKR1C3, pointing to a new direction of drug development using BBR as the lead compound.