Cynanchum wallichii Wight and CW1 reversed docetaxel resistance effects by inhibiting P-gp and promoting PI3K/Akt-mediated apoptosis in prostate cancer.

Abstract

Cynanchum wallichii (CW) is a traditional Chinese medicine which is widely used for treating arthrophlogosis, traumatic injury, and other conditions. Herein, we investigate the effects and mechanisms of CW and its bioactive constituent CW1 in reversing docetaxel (DTX) resistance in prostate cancer (PCa) cells. We investigated the reversal effects of CW and its bioactive constituent CW1 on 22Rv1/DTX cells in vitro and in vivo. We also explored the underlying mechanism by evaluating drug sensitivity, cell proliferation, efflux transporter P-glycoprotein (P-gp), and molecular signaling involved in apoptosis-related protein expression. CW and its bioactive constituent CW1 reversed DTX resistance in PCa 22Rv1/DTX cells by directly binding to the efflux transporter P-gp and by inhibiting the expression of P-gp. This significantly increased the intracellular concentration of DTX and inhibited the malignant proliferation of 22Rv1/DTX cells. In addition, DTX + CW/CW1 co-treatment significantly increased the apoptosis effects in 22Rv1/DTX cells by regulating the relative expressions of BAX, Bcl2, cytochrome C, and caspase 3/9. Furthermore, both CW and CW1 enhanced the in vivo therapeutic effect of DTX in the 22Rv1/DTX cell xenograft while alleviating the side effects of liver and kidney damage caused by DTX. Our results suggest that CW and its bioactive constituent CW1 enhance the antitumor activity of DTX by reducing P-gp expression and promoting phosphoinositide 3-kinase/Akt-mediated apoptosis in vitro and in vivo. Our results firstly confirm that CW1, as a natural bioactive substance, holds promise as an adjuvant drug for treating high-load metastatic and castration-resistant PCa.