Gugulipid (GL), extract of Indian Ayurvedic medicinal plant Commiphora mukul, has been used to treat a variety of ailments. We report an anticancer effect and mechanism of GL against human
prostate cancer cells. Treatment with GL significantly inhibited the viability of human
prostate cancer cell line LNCaP (
androgen-dependent) and its
androgen-independent variant (C81) with an IC(50) of ∼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-G(0)/G(1)-
DNA fraction, and cleavage of
poly(ADP-ribose) polymerase. The GL-induced apoptosis was associated with
reactive oxygen species (ROS) production and c-Jun NH(2)-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 the 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.