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Research ArticleArticle

Reactive Oxygen Species-Dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora mukul in Human Prostate Cancer Cells Is Regulated by c-Jun N-Terminal Kinase

Dong Xiao, Yan Zeng, Lakshmi Prakash, Vladmir Badmaev, Muhammed Majeed and Shivendra V. Singh
Molecular Pharmacology March 2011, 79 (3) 499-507; DOI: https://doi.org/10.1124/mol.110.068551
Dong Xiao
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Yan Zeng
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Lakshmi Prakash
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Vladmir Badmaev
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Muhammed Majeed
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Shivendra V. Singh
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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

  • ↵Embedded Image 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.

  • 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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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Reactive Oxygen Species-Dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora mukul in Human Prostate Cancer Cells Is Regulated by c-Jun N-Terminal Kinase

Dong Xiao, Yan Zeng, Lakshmi Prakash, Vladmir Badmaev, Muhammed Majeed and Shivendra V. Singh
Molecular Pharmacology March 1, 2011, 79 (3) 499-507; DOI: https://doi.org/10.1124/mol.110.068551

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Research ArticleArticle

Reactive Oxygen Species-Dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora mukul in Human Prostate Cancer Cells Is Regulated by c-Jun N-Terminal Kinase

Dong Xiao, Yan Zeng, Lakshmi Prakash, Vladmir Badmaev, Muhammed Majeed and Shivendra V. Singh
Molecular Pharmacology March 1, 2011, 79 (3) 499-507; DOI: https://doi.org/10.1124/mol.110.068551
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