Deguelin-Induced Inhibition of Cyclooxygenase-2 Expression in Human Bronchial Epithelial Cells

Lee, Ho‐Young; Suh, Young Ah; Kosmeder, Jerome W.; Pezzuto, John M.; Hong, Waun Ki; Kurie, Jonathan M.

doi:10.1158/1078-0432.ccr-0833-3

Cited by 58 publications

(49 citation statements)

References 23 publications

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“…Furthermore, our results that deguelin down-regulates cyclin D1 expression are in agreement with previous reports (13) that showed that downregulation of cyclin D1 is responsible for cell cycle arrest at the G 0 /G 1 phase. Similarly, our findings that deguelin suppresses NF-B-regulated COX-2 expression are in agreement with a previous report involving human bronchial epithelial cells (12).…”

Section: Discussionsupporting

confidence: 94%

Deguelin, an Akt Inhibitor, Suppresses IκBα Kinase Activation Leading to Suppression of NF-κB-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion

Nair

Shishodia

Ahn

et al. 2006

The Journal of Immunology

109

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Deguelin, a constituent of the bark of the African plant Mundulea sericea (Leguminosae), exhibits antiproliferative and anticarcinogenic activities through a mechanism that is not well understood. Because various steps in carcinogenesis are regulated by NF-κB, we postulated that the activity of deguelin is mediated through this transcription factor. We found that deguelin suppressed NF-κB activation induced by carcinogens, tumor promoters, growth factors, and inflammatory stimuli. This suppression was not cell-type specific, because NF-κB activation was suppressed in both lymphoid and epithelial cells. Moreover, constitutive NF-κB activation was also blocked by deguelin. The suppression of TNF-induced NF-κB activation by deguelin occurred through the inhibition of the activation of IκBα kinase, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-dependent reporter gene expression. Deguelin also suppressed the NF-κB reporter activity induced by TNFR1, TNFR-associated death domain, TNFR-associated factor 2, and IκBα kinase, but not that induced by p65. The inhibition of NF-κB activation thereby led to the down-regulation of gene products involved in cell survival, proliferation, and invasion. Suppression of these gene products by deguelin enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results demonstrate that deguelin inhibits the NF-κB activation pathway, which may explain its role in the suppression of carcinogenesis and cellular proliferation.

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Section: Discussionsupporting

confidence: 94%

Deguelin, an Akt Inhibitor, Suppresses IκBα Kinase Activation Leading to Suppression of NF-κB-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion

Nair

Shishodia

Ahn

et al. 2006

The Journal of Immunology

109

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“…In contrast, deguelin treatment even at 1 mM showed significant decrease in lung epithelial cell lines. Similarly, cytotoxic effects of L80 on vascular endothelial and retinal epithelial cells were less compared with deguelin ( Fig Blockade of the C-terminal Hsp90 ATP Binding Domain by L80 effects on normal HBE cells at in vitro concentrations that are attainable in vivo (Lee et al, 2004). Hence, we first examined the effects of L80 on viability of NSCLC cell lines (i.e., H1299, A549, H460, and H226B).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90

et al. 2015

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The clinical benefit of current anticancer regimens for lung cancer therapy is still limited due to moderate efficacy, drug resistance, and recurrence. Therefore, the development of effective anticancer drugs for first-line therapy and for optimal second-line treatment is necessary. Because the 90-kDa molecular chaperone heat shock protein (Hsp90) contributes to the maturation of numerous mutated or overexpressed oncogenic proteins, targeting Hsp90 may offer an effective anticancer therapy. Here, we investigated antitumor activities and toxicity of a novel deguelinderived C-terminal Hsp90 inhibitor, designated L80. L80 displayed significant inhibitory effects on the viability, colony formation, angiogenesis-stimulating activity, migration, and invasion of a panel of non-small cell lung cancer cell lines and their sublines with acquired resistance to paclitaxel with minimal toxicity to normal lung epithelial cells, hippocampal cells, vascular endothelial cells, and ocular cells. Biochemical analyses and molecular docking simulation revealed that L80 disrupted Hsp90 function by binding to the C-terminal ATP-binding pocket of Hsp90, leading to the disruption of the interaction between hypoxia-inducible factor (HIF)-1a and Hsp90, downregulation of HIF-1a and its target genes, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF2), and decreased the expression of various Hsp90 client proteins. Consistent with these in vitro findings, L80 exhibited significant antitumor and antiangiogenic activities in H1299 xenograft tumors. These results suggest that L80 represents a novel C-terminal Hsp90 inhibitor with effective anticancer activities with minimal toxicities.

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“…Furthermore, deguelin selectively blocks Akt activity in a phosphoinositide 3-kinase (PI3K)-dependent or -independent manner, thereby, diminishing the activity of a major anti-apoptotic pathway (9,10). Additionally, deguelin strongly inhibits cyclooxygenase (COX)-2 expression in squamous HBE cells, without affecting COX-1 protein level (11).…”

Section: Introductionmentioning

confidence: 99%

Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer

Li¹

2010

Oncol Rep

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Abstract. Gastric cancer is often diagnosed in locally advanced or metastatic stages, which preludes a poor prognosis. As only 10% of patients with advanced gastric cancer treated with chemotherapy survive 2 years, new approaches for preventing and controlling the disease are required. We therefore, assessed in gastric cancer cells the chemotherapeutic potential and mechanism of deguelin, a rotenoid of the flavonoid family isolated from several plant species. The effect of deguelin on the proliferation and apoptosis in the gastric cancer cells were assessed by MTT and flow cytometry. The growth of gastric cancer cells (SNU-484, AGS and MKN-28) was inhibited by deguelin in a dose-dependent manner. G 2 /M phase arrest was induced by deguelin in gastric cancer cells. Deguelin (1 μM) induced chromatin condensation and DNA fragmentation. Also the exposure to 1 μM deguelin resulted in the increase in earlyapoptotic cells (Annexin V-positive/Propidium iodidenegative) after 24 h, compared to the cells in the control medium (31 versus 12%). Deguelin-induced apoptosis involved the caspase-9 and caspase-3 pathways in gastric cancer cells. Akt phosphorylation, hypoxia-inducible factor-1· accumulation, and vascular endothelial growth factor expression in gastric cancer cells was inhibited by deguelin. Taken together, deguelin showed anticancer activity in gastric cancer cells, which is correlated with the inhibition of angiogenesis and induction of apoptosis. Deguelin may be a potential agent in inhibiting the progression of gastric cancer by virtue of its activity on these crucial cell characteristics.

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Deguelin-Induced Inhibition of Cyclooxygenase-2 Expression in Human Bronchial Epithelial Cells

Cited by 58 publications

References 23 publications

Deguelin, an Akt Inhibitor, Suppresses IκBα Kinase Activation Leading to Suppression of NF-κB-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion

Deguelin, an Akt Inhibitor, Suppresses IκBα Kinase Activation Leading to Suppression of NF-κB-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion

Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90

Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer

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