Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase

Gerhäuser, Clarissa; Mar, Woongchon; Lee, S K; Suh, Nanjoo; Luo, Yan; Kosmeder, Jerrome W.; Luyengi, Lumonadio; Fong, Harry H. S.; Kinghorn, A. Douglas; Moriarty, Robert M.

doi:10.1038/nm0395-260

Cited by 135 publications

(110 citation statements)

References 22 publications

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“…23 It is a potent inhibitor of ODC activity, with an IC 50 of 0.7 ng/ml in cultured mouse 308 cells. 24 In addition, it inhibits 12-O-tetradecanoylphorbol 13-acetate-induced ODC activity in mouse skin epidermis. 25 Previous studies have shown that deguelin effectively inhibited the development of carcinogen-induced precancerous lesions in…”

Section: Abstract: Deguelin; Aberrant Crypt Foci; Hexosaminidase; Cfmentioning

confidence: 99%

Deguelin suppresses the formation of carcinogen‐induced aberrant crypt foci in the colon of CF‐1 mice

Murillo

Kosmeder

Pezzuto

et al. 2003

Intl Journal of Cancer

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Deguelin [(7aS,BaS)-13,13a-dihydro-9,10-dimethoxy-3,3-dimethyl-3H-Bis[1]benzopyrano[3,4-b:6 ,5 -e]pyran-7(7aH)-one], a naturally occurring rotenone, has shown chemopreventive efficacy in several in vivo and in vitro models. In this report, the effectiveness of deguelin at inhibiting the development of AOM-induced colonic ACF was investigated in CF-1 mice. Loss of hex activity was assessed as a second biomarker. In an initial experiment, animals were given s.c. injections of AOM (10 mg/kg body weight) once a week for 2 weeks to induce ACF. Deguelin and vehicle (corn oil) were administered i.g. 7 days a week. Treatment was initiated 2 weeks prior to the first dose of carcinogen and continued for the duration of the study. The mean number of ACF for the control group was 29.0 ؎ 4.3, whereas the mean numbers of ACF in the deguelin groups were 24.8 ؎ 2.7, 7.2 ؎ 1.5 and 4.6 ؎ 1.4 at doses of 2.5, 5.0 and 10.0 mg/kg body weight, respectively. In a similar manner, treatment with deguelin significantly (p < 0.001) suppressed the appearance of hexcrypts in a dose-dependent manner. In a second study, the ability of deguelin to block the initiation and promotion stages of colon carcinogenesis was investigated. Greatest inhibition was observed when deguelin was administered during the promotional stage (73.3%, p < 0.001). These results demonstrate that deguelin is an efficacious chemopreventive agent against colon carcinogenesis. © 2002 Wiley-Liss, Inc. Key words: deguelin; aberrant crypt foci; hexosaminidase; CF-1 mice; colon; carcinogenesisColon cancer is the third most common cancer in the United States. It is estimated that 107,600 new cases of colon cancer will be diagnosed in 2002 and that 48,100 people will die from this disease. 1 In the past decade, many studies have helped to define the molecular mechanisms underlying this malignancy. 2 With a better understanding of the molecular pathogenesis of this disease, new strategies for its prevention and treatment continue to emerge. Identification of novel cancer-preventive agents has received considerable attention in the past 30 years. [3][4][5][6] Likewise, the development of surrogate end points or biomarkers that can be used for screening novel agents in experimental models has been extremely important to the field of chemoprevention.ACF have been identified on the colonic mucosal surface of rodents treated with carcinogens and shown to be one of the earliest recognizable lesions in the colon; furthermore, the carcinogens (e.g., AOM) that induce ACF also induce colon cancer in rodents. 7 Several lines of evidence strongly suggest that ACF are good intermediate biomarkers of colon cancer in both rodents 7 and humans. 8 Morphologically, ACF are distinguishable from normal crypts by their increased size and the more elliptical shape of the luminal opening, with a thicker lining of epithelial cells. 9 ACF contain elements of dysplasia (evident by alterations in enzyme activity) and express mutations in the APC gene and the ras oncogene, which suggests that they are part...

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Section: Abstract: Deguelin; Aberrant Crypt Foci; Hexosaminidase; Cfmentioning

confidence: 99%

Deguelin suppresses the formation of carcinogen‐induced aberrant crypt foci in the colon of CF‐1 mice

Murillo

Kosmeder

Pezzuto

et al. 2003

Intl Journal of Cancer

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“…Rotenoids are known not only as toxicants but also as candidate anticancer agents based on three observations: dietary rotenone reduces the background incidence of liver tumors in mice (6) and mammary tumors in rats (7), prevents cell proliferation induced by a peroxisome proliferator in mouse liver (6), and deguelin and three of its derivatives inhibit phorbol ester-induced ornithine decarboxylase (ODC) activity as a measure of cancer chemopreventive potency (8,9). The commercial rotenone-containing botanicals or extracts thereof are complex mixtures of rotenoids and other natural products that provide the opportunity for action on multiple biochemical targets.…”

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confidence: 99%

Anticancer action of cubé insecticide: Correlation for rotenoid constituents between inhibition of NADH:ubiquinone oxidoreductase and induced ornithine decarboxylase activities

Fang

Casida

1998

Proc. Natl. Acad. Sci. U.S.A.

167

130

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Rotenone and rotenoid-containing botanicals, important insecticides and fish poisons, are reported to have anticancer activity in rats and mice. The toxic action of rotenone is attributed to inhibition of NADH:ubiquinone oxidoreductase activity and the purported cancer chemopreventive effect of deguelin analogs has been associated with inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity. This study defines a possible relationship between these two types of activity important in evaluating the toxicology of rotenoid pesticides and the suitability of the anticancer model. Fractionation of cubé resin (the commercial rotenoid pesticide) establishes that the activity in both assays is due primarily to rotenone (IC 50 ‫؍‬ 0.8-4 nM), secondarily to deguelin, and in small part to rotenolone and tephrosin. In addition, the potency of 29 rotenoids from cubé insecticide for inhibiting NADH:ubiquinone oxidoreductase in vitro assayed with bovine heart electron transport particles satisfactorily predicts their potency in vivo in the induced ODC assay using noncytotoxic rotenoid concentrations with cultured MCF-7 human breast cancer cells (r ‫؍‬ 0.86). Clearly the molecular features of rotenoids essential for inhibiting NADH:ubiquinone oxidoreductase are similar to those for blocking ODC induction. This apparent correlation extends to 11 f lavonoids and stilbenoids from cubé resin (r ‫؍‬ 0.98) and genistein and resveratrol except for lower potency and less selectivity than the rotenoids relative to cytotoxicity. These findings on cubé insecticide constituents and our earlier study comparing rotenone and pyridaben miticide indicate that inhibition of NADH:ubiquinone oxidoreductase activity lowers the level of induced ODC activity leading to the antiproliferative effect and anticancer action.

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“…Rotenoids, which are typically insecticidal agents, constitute a class of compounds from the flavonoid family and have cancer chemopreventive and anticancer activities (3,4). Deguelin is a natural rotenoid which has been isolated from several plant species, including Mundulea sericea (Leguminosae; Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1). Recently, deguelin has been found to exhibit strong cancer chemopreventive and antitumor activities in vitro and in vivo in various model systems (2)(3)(4)(5)(6)(7)(8)(9). However, the antitumor effects of deguelin against multiple myeloma have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Deguelin, a natural rotenoid, inhibits mouse myeloma cell growth in vitro via induction of apoptosis

et al. 2012

Oncology Letters

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Abstract. Deguelin is a naturally occurring rotenoid with strong cancer chemopreventive and antitumor activities. In the present study, we investigated the antitumor activity of deguelin against MPC-11 murine myeloma cells and the possible mechanism of action in vitro. Our results revealed that deguelin inhibited the proliferation of MPC-11 cells in a concentration-and time-dependent manner and caused the apoptotic death of MPC-11 cells. Following exposure to deguelin, the phosphorylation of Akt was decreased. The inhibition of cell growth may be associated with decreased levels of phosphorylated Akt. Deguelin-induced apoptosis was characterized by the upregulation of Bax, downregulation of Bcl-2 and activation of caspase-3. In conclusion, deguelin inhibits murine myeloma cell proliferation by inducing apoptosis via regulation of the Bax/Bcl-2 ratio and by inhibition of the activation of Akt. Its potential as an anticancer agent against multiple myeloma warrants further investigation.

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Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase

Cited by 135 publications

References 22 publications

Deguelin suppresses the formation of carcinogen‐induced aberrant crypt foci in the colon of CF‐1 mice

Deguelin suppresses the formation of carcinogen‐induced aberrant crypt foci in the colon of CF‐1 mice

Anticancer action of cubé insecticide: Correlation for rotenoid constituents between inhibition of NADH:ubiquinone oxidoreductase and induced ornithine decarboxylase activities

Deguelin, a natural rotenoid, inhibits mouse myeloma cell growth in vitro via induction of apoptosis

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