Posted August 11, 2015
Dr. Haitao Zhang, Tulane University
Advanced prostate cancer is notorious for developing resistance to therapies. Therefore, it is important to understand and target resistance mechanisms in the pursuit of more effective treatments. One of the underpinnings for the development of resistance is that cancer cells rely on multiple intracellular pathways for growth and survival. Development of treatment strategies that can target several pathways concurrently is important since shutting down one pathway can cause cancer cells to turn on alternative pathways, rendering the initial treatment ineffective. Two key cancer promoting pathways in prostate cancer, the androgen receptor (AR) pathway and the PI3K/AKT pathway, act in this manner through reciprocal inhibition. While one pathway is activated by the cancer cells to promote tumor growth, the other is put into a "reserve" mode acting as a failsafe to continue tumor development if the initial pathway is inhibited. Dr. Haitao Zhang of Tulane University has shown that the low cost natural product, berberine, simultaneously inhibits both pathways in cell culture and animal models, suggesting its possible use in the treatment or prevention of prostate cancer. In addition, berberine has been shown to be effective against a predominant AR splice variant, AR-V7, which plays an important role in mediating resistance to the AR antagonist enzalutamide.
Before berberine can transition into clinical application, the mechanism of action for inhibiting both pathways must be understood. With support from a FY11 Idea Development Award, Dr. Zhang and his research team have been conducting in-depth studies to understand how the molecule exerts its effects in prostate cancer. To date, the multi-disciplinary team has observed that berberine reduces the expression of full length AR and phosphorylated AKT. By limiting the presence of both AR and AKT proteins simultaneously, berberine effectively shuts down both key pathways, and thwarts cancer development and progression in animal models of prostate cancer. In addition to this, they observed that berberine also contributed to the reduction of the truncated AR-V7 splice variant, suggesting berberine could sensitize prostate cancer to existing treatments such as abiraterone, enzalutamide, and docetaxel.
Additional studies to further elucidate the mechanism of action are currently underway and should assist in transitioning the investigations to a clinical setting; with the ultimate goal that berberine will be available as a low cost treatment option for men with prostate cancer.
Figure 1. Berberine inhibits the development of Pten-null tumors and down-regulates the expression of AR and AKT. A, Representative images and average tumor burden from Pten-null mice treated with DMSO (control) or berberine (BBR). B, prostatic tissues were analyzed by immunohistochemistry (IHC) staining for the expression of AR and AKT. C & D, quantitation of IHC staining for AR and AKT, respectively. **, P<0.01.
Li J, Cao B, Liu X, Fu X, Xiong Z, Chen L, Sartor O, Dong Y, Zhang H. Berberine Suppresses Androgen Receptor Signaling in Prostate Cancer. Mol. Cancer Ther. 2011. Aug; 10(8): 1346-56.
Zhang, G., Liu, X., Li, J., Ledet, E., Alvarez, X., Qi, Y., Fu, X., Sartor, O., Dong, Y., & Zhang, H. (2015). Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents. Oncotarget, published online June 22, 2015.
Public and Technical Abstracts: Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer