Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats

Udeani, George; Zhao, Guangjie; Shin, Young Geun; Kosmeder, Jerome W.; Beecher, Christopher W.W.; Kinghorn, A. Douglas; Moriarty, Robert M.; Moon, Richard C.; Pezzuto, John M.

doi:10.1007/s002800000187

Cited by 59 publications

(46 citation statements)

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“…53 The results of this study showed that 10 À6 M deguelin is achievable in a variety of tissues in vivo after intravenous delivery. Moreover, this dosage is not toxic to rats.…”

Section: Discussionmentioning

confidence: 81%

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

et al. 2007

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We investigated if deguelin, a naturally occurring rotenoid, was able to inhibit nuclear factor kappa B (NF-jB)-binding protein (IjBa) expression and to induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro. Deguelin-induced cell death in the majority of B-CLL cells and was found to be more toxic toward B-CLL cells than to the normal mononuclear or B-cells, suggesting selectivity towards the malignant cells. Deguelin was found to reduce IjBa protein expression, and thus interacts with the NFjB pathway. The induced apoptosis was characterized by processing of caspase-9 and -3 and poly-(ADP)-ribose-polymerase cleavage. Exposure of B-CLL cells to deguelin resulted in Bcl2-associated protein (Bax) conformational changes and downregulation of the key survival protein myeloid cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. Deguelin retained its ability to induce apoptosis in B-CLL cells in the presence of interleukin-4, a pro-survival cytokine in B-CLL, and when cultured with 50% human serum. These data indicate that deguelin is able to induce apoptosis in B-CLL cells in the presence of pro-survival signals and thus merits further investigation for clinical application either as a single agent or in combination with other anticancer agents.

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“…53 The results of this study showed that 10 À6 M deguelin is achievable in a variety of tissues in vivo after intravenous delivery. Moreover, this dosage is not toxic to rats.…”

Section: Discussionmentioning

confidence: 81%

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

et al. 2007

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“…In addition, the insecticidal activity of deguelin and other rotenoids and the systemic toxicities, such as neurological toxicities including somnolence and ataxia (38) are probably due to the potent inhibition of NADH-dehydrogenase and concomitant depletion of intracellular ATP. Deguelin has shown an IC 50 as low as 33 nM for NADH-dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Suh

Kosmeder

et al. 2004

Clinical Cancer Research

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The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.

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“…This study showed for the first time that the antiproliferative, proapoptotic, and antiinvasive effects of deguelin may be mediated through the suppression of NF-B and NF-B-regulated gene products. Considering the pharmacologic safety of deguelin (64), this agent should be further explored as a potential chemopreventive agent.…”

Section: Discussionmentioning

confidence: 99%

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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Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats

Abstract: An initial pharmacokinetic investigation of deguelin showed that this rotenoid has a relatively long MRT and half-life in plasma in the rat. The compound distributed in the tissues and excreted as metabolites, mainly via the feces.

Cited by 59 publications

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Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

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

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

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