Gugulipid (GL), extract of Indian Ayurvedic medicinal plant Commiphora mukul, has been used to treat a variety of ailments. We now report anti-cancer effect and mechanism of GL against human prostate cancer cells. Treatment with GL significantly inhibited viability of human prostate cancer cell line LNCaP (androgen-dependent) and its androgen-independent variant (C81) with an IC50 ~ 1 μM (24 h treatment) at pharmacologically relevant concentrations standardized to its major active constituent z-guggulsterone. The GL-induced growth inhibition correlated with apoptosis induction as evidenced by an increase in cytoplasmic histone-associated DNA fragmentation and sub-G0/G1DNA fraction, and cleavage of poly-(ADP-ribose)-polymerase (PARP). The GL-induced apoptosis was associated with reactive oxygen species (ROS) production and c-Jun NH2-terminal kinase (JNK) activation. The induction of proapoptotic Bcl-2 family proteins Bax and Bak and a decrease of antiapoptotic Bcl-2 protein Bcl-2 were observed in GL-treated cells. SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double knockout mice were significantly more resistant to GL-induced cell killing compared with wild type cells. It is interesting to note that a representative normal prostate epithelial cell line PrEC was relatively more resistant to GL-mediated cellular responses compared with prostate cancer cells. The GL treatment caused activation of JNK that functioned upstream of Bax activation in apoptosis response. The GL-induced conformational change of Bax and apoptosis were significantly suppressed by genetic suppression of JNK activation. In conclusion, the present study indicates that ROS-dependent apoptosis by GL is regulated by JNK signaling axis.
- MAP Kinase
- Jun Kinase
- Mitochondrial toxins
- Oxidative stress/antioxidants
- Mechanisms of cell killing/apoptosis
- Received August 31, 2010.
- Revision received November 24, 2010.
- Accepted November 29, 2010.
- The American Society for Pharmacology and Experimental Therapeutics