Deguelin inhibits the growth of colon cancer cells through the induction of apoptosis and cell cycle arrest

Murillo, Genoveva; Salti, George I.; Kosmeder, Jerome W.; Pezzuto, John M.; Mehta, Rajendra G.

doi:10.1016/s0959-8049(02)00192-2

Cited by 91 publications

(75 citation statements)

References 24 publications

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“…Furthermore, studies on the transcription factor E2F-1 and pRb established that deguelin may exert its effects by regulating phosphorylation of pRb and thus increasing binding and subsequent inactivation of E2F-1. 26 Further investigations on the mechanism of action mediated by deguelin in suppressing precancerous lesions are warranted.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…3,4 The plant derived rotenoid deguelin, most commonly used as an insecticide in Africa and South America, has been isolated from several plant species, including Mundulae sericea (Leguminosae). 5 So far, the potential of deguelin as a cancer chemotherapeutic agent was suggested in several cancers, including colon cancer 6 and skin or mammary tumorigenesis models. 7 In addition, deguelin was suggested to be useful for chemoprevention and the induction of apoptosis in lung carcinogenesis and for therapy in confirmed lung cancer.…”

Section: Introductionmentioning

confidence: 99%

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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“…The researchers also observed that deguelin promoted cell cycle arrest in colon and lung cancer cells, which was followed by apoptosis induction. In colon cancer cells, deguelin arrested the cell cycle at the G 0 /G 1 phase (8). In this study, we found that SNU-484 cells treated with deguelin were arrested at the G 2 /M phase.…”

Section: Discussionmentioning

confidence: 49%

“…It also increases the sensitivity of leukemia cells to chemotherapeutic agents (7) and suppresses the growth of human colon cancer cells (8). Deguelin blocks the proliferation of premalignant and malignant human bronchial epithelial (HBE) cells by inducing apoptosis (9).…”

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 inhibits the growth of colon cancer cells through the induction of apoptosis and cell cycle arrest

Cited by 91 publications

References 24 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

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

Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer

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