A Standardized Wedelia chinensis Extract Overcomes the Feedback Activation of HER2/3 Signaling upon Androgen-Ablation in Prostate Cancer
Androgen receptor (AR)-mediated signaling play an essential role in prostate cancer for survival, growth, and invasion. Crosstalk between the AR and other signaling pathways in prostate cancer (PCa) severely affects the therapeutic outcome of hormonal therapy. Although anti-androgen therapy prolongs overall survival in PCa patients, resistance rapidly develops and is often associated with increased AR expression and upregulation of the HER2/3-AKT signaling pathway. However, single-agent therapy targeting AR, HER2/3 or AKT usually fails due to the reciprocal feedback loop. Here, we demonstrated that a standardized herbal extract, named WCE, effectively disrupted the AR, HER2/3, and AKT signaling networks and therefore enhanced the therapeutic efficacy of androgen ablation in PCa. Furthermore, WCE remained effective in suppressing AR and HER2/3 signaling in an in vivo adapted castration-resistant PCa cells that were insensitive to androgen withdrawal and a second-line antiandrogen, enzalutamide. This study provides preclinical evidence that the use of a defined, single plant-derived extract can augment the therapeutic efficacy of castration with significantly prolonged progression-free survival. These data also establish a solid basis for using WCE as a candidate agent in clinical studies.Co-researchers:Chin-Hsien Tsai, Sheue-Fen Tzeng, Shih-Chuan Hsieh, Chia-Jui Tsai, Yu-Chih Yang, Mong-Hsun Tsai