Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone resorption is commonly associated with aging and with certain types of cancer, including multiple myeloma and breast cancer. What induces bone resorption is not fully understood, but the role of osteoclasts is well established. Recently, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), a member of the tumor necrosis factor superfamily, was implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. Guggulsterone [4,17(20)-pregnadiene-3,16-dione], isolated from the guggul tree Commiphora mukul and used to treat osteoarthritis and bone fractures, was recently shown to antagonize the farnesoid X receptor, decrease the expression of bile acid-activated genes, and suppress the NF-kappaB activation induced by various carcinogens. We investigated whether guggulsterone could modulate RANKL signaling and osteoclastogenesis induced by RANKL or tumor cells. We found that treatment of monocytes with guggulsterone suppressed RANKL-activated NF-kappaB activation (as indicated by gel-shift assay) and that this suppression correlated with inhibition of IkappaBalpha kinase and phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. Guggulsterone also suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. Suppression of osteoclastogenesis by the NF-kappaB-specific inhibitory peptide implies a link between NF-kappaB and osteoclastogenesis. Finally, differentiation to osteoclasts induced by coincubating human breast tumor cells (MDA-MB-468) or human multiple myeloma (U266) cells with monocytes was also completely suppressed by guggulsterone. Collectively, our results indicate that guggulsterone suppresses RANKL and tumor cell-induced osteoclastogenesis by suppressing the activation of NF-kappaB.
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PMID:Guggulsterone inhibits osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand and by tumor cells by suppressing nuclear factor-kappaB activation. 3018 92

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22