Abstract
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 IC50 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-G0/G1-DNA fraction, and cleavage of poly(ADP-ribose) polymerase. 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 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.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Institutes of Health National Cancer Institute [Grant R21-CA143104].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.068551.
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ABBREVIATIONS:
- GL
- gugulipid
- CDCFDA
- (5-(and-6)-carboxy-2′,7′-dichloroluorescein diacetate, succinimidyl ester
- HE
- hydroethidine
- PARP
- poly(ADP-ribose) polymerase
- DMSO
- dimethyl sulfoxide
- DCF
- 2′,7′-dichlorodihydrofluorescein
- JNK
- c-Jun N-terminal kinase
- MAPK
- mitogen-activated protein kinase
- JNKK2
- c-Jun N-terminal kinase kinase 2
- PrEC
- normal human prostate epithelial cell line
- ROS
- reactive oxygen species
- ANOVA
- analysis of variance
- ERK
- extracellular signal-related kinase
- MEF
- mouse embryonic fibroblast
- DKO
- double knockout
- WT
- wild type
- NAC
- n-acetyl cysteine
- z-Gug
- z-guggulsterone
- siRNA
- small interfering RNA
- CHAPS
- 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
- mTOR
- mammalian target of rapamycin
- SV40
- simian virus 40.
- Received August 31, 2010.
- Accepted November 29, 2010.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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