Guggulsterone Inhibits NF- B and I B Kinase Activation, Suppresses Expression of Anti-apoptotic Gene Products, and Enhances Apoptosis*

نویسنده

  • Bharat B. Aggarwal
چکیده

Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NFB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NFB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NFB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NFB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NFB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NFB activation expressed in most tumor cells. Through inhibition of I B kinase activation, this steroid blocked I B phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NFB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NFB and NFB-regulated gene products, which may explain its anti-inflammatory activities.

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تاریخ انتشار 2004