Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis y HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice

Narisawa, Tomio; Fukaura, Yoko; Terada, Kunihiko; Umezawa, Akiko; Tanida, Noritoshi; Yazawa, Kazunaga; Ishikawa, Chikako

doi:10.1093/carcin/15.9.2045

Cited by 70 publications

(29 citation statements)

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“…Although the effect of pravastatin on the growth of experimental mammary tumors or gastrointestinal tumors in rodents has not been reported, at physiological concentrations, pravastatin does not inhibit the proliferation of human breast cancer cells (50) or gastric carcinoma cells (51) in culture. Interestingly, pravastatin does inhibit the growth of colon tumors in rats (52) and mice (53), in keeping with its ability to inhibit HMG-CoA reductase in intestinal cells (49,54). A reduced risk of colorectal cancer has also been reported in one human trial of pravastatin (16).…”

Section: Fig 4 Mevalonate Increases Cdk-2 Activitymentioning

confidence: 74%

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Duncan¹,

El-Sohemy²,

Archer

2004

Journal of Biological Chemistry

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Malignant cells are known to have elevated rates of mevalonate synthesis because of increased levels and catalytic efficiency of 3-hydroxy-3-methylglutaryl-CoA reductase. Whether this increased mevalonate synthesis occurs as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown. To address this question, we administered mevalonate via miniosmotic pumps to nude mice inoculated with MDA-MB-435 human cancer cells. After 13 weeks of growth, tumors in mevalonatetreated mice were significantly larger than tumors in saline-treated, control mice (1.52 ؎ 0.26 g versus 0.81 ؎ 0.27 g respectively, p < 0.05). The cancer cells treated in culture with mevalonate also demonstrated increased proliferation rates associated with accelerated entry of cells into S phase. These cells had enhanced total and cyclin A-immunoprecipitable cyclin-dependent kinase-2 (CDK-2) activity, increased activating phosphorylation of CDK-2, and decreased inhibitory binding of CDK-2 to p21 Cip1 . Our findings demonstrate that mevalonate promotes tumor growth and suggest that an increase in mevalonate synthesis in extrahepatic tissues following cholesterol-lowering therapy may explain the elevated risk of cancer shown in some studies.HMG-CoA 1 reductase is the rate-limiting enzyme in cholesterol biosynthesis that catalyzes the formation of mevalonate (1). In addition to being a precursor of cholesterol, mevalonate is required for a number of cellular processes including DNA synthesis and proliferation (2). Mevalonate is also the precursor of non-sterol isoprenoids that have a variety of functions including prenylation of growth-regulating proteins and oncoproteins (3, 4). Elevated mevalonate synthesis has been reported in malignant breast (5), lung (6), leukemia and lymphoma (7), and hepatoma cells (8). Whether increased mevalonate synthesis occurs in malignant cells simply as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown.HMG-CoA reductase is regulated through a multivalent feedback mechanism that is controlled, in part, by intracellular cholesterol levels (1). Cells meet their cholesterol requirements by de novo synthesis or by uptake from plasma of cholesterolrich low density lipoprotein. A fall in circulating levels of low density lipoprotein causes a decrease in its uptake, and the resultant drop in intracellular cholesterol levels leads to a compensatory stimulation of mevalonate synthesis through upregulation of HMG-CoA reductase (1). We have shown that a diet rich in cholesterol that raised circulating cholesterol levels also significantly decreased mammary gland HMG-CoA reductase activity (5) and inhibited the development of chemically induced mammary tumors in rats (5, 9). We have also shown in mice that a diet rich in cholesterol protects against the development of chemically induced preneoplastic lesio...

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Section: Fig 4 Mevalonate Increases Cdk-2 Activitymentioning

confidence: 74%

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Duncan¹,

El-Sohemy²,

Archer

2004

Journal of Biological Chemistry

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“…Similarly, in our recent study simvastatin administered in the diet at a dose of 180 mg/kg significantly reduced mammary tumor frequency by 80.5% and incidence by 58.5% when compared to controls (Kubatka et al 2011). In 1,2-dimethylhydrazine-induced colon car- cinogenesis in ICR mice, simvastatin and pravastatin significantly reduced tumor frequency (Narisawa et al 1994). Pravastatin has been shown to reduce the incidence and volume of N-nitrosomorpholine-induced rat hepatic neoplastic nodules (Tatsuta et al 1998) and NMU-induced rat colon carcinogenesis (Narisawa et al P. Kubatka et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

et al. 2011

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Epidemiological studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, play a role in inhibition of several human neoplasia including breast cancer. In this study, chemopreventive effects of atorvastatin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Atorvastatin was administered in the diet at two concentrations: 10 mg/kg (ATOR 10) and 100 mg/kg (ATOR 100). Atorvastatin treatment began 8 days prior to carcinogen administration and subsequently continued for 15 weeks till the end of the experiment. Atorvastatin at a higher dose suppressed tumor frequency by 80.5% (P = 0.0008) and tumor incidence by 49.5% (P = 0.015), and extended latency period by 14 days (P = 0.076) when compared to the control group. Atorvastatin at a lower dose did not significantly alter tumor parameters in comparison with the control group. In the specimens of mammary tumors, atorvastatin (in the ATOR 100 group) significantly decreased mRNA expression of Bcl-2 gene but non-significantly increased Bax mRNA expression compared to control group. Atorvastatin administration did not alter serum concentration of triacylglycerols, total cholesterol, and LDL cholesterol in comparison with controls. This study is the first report on tumor suppressive effect of atorvastatin in rat mammary carcinogenesis.

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“…32,33 These data further suggest these agents may have a role in cancer prophylaxis as well as therapy. 19,[32][33][34][35] Indeed, recent analyses have demonstrated that inhibitors of HMG-CoA reductase can directly block tumor cell growth both in vitro and in vivo. In this review, we will focus on the antiproliferative activity of the statins, the mechanism of statin-induced apoptosis, and the application of statin therapy as an anti-cancer agent.…”

Section: Figurementioning

confidence: 99%

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

et al. 2002

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The statin family of drugs target HMG-CoA reductase, the ratelimiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

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Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis y HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice

Cited by 70 publications

References 0 publications

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

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