Atorvastatin Induces Apoptosis In Vitro and Slows Growth of Tumor Xenografts but Not Polyp Formation in Min Mice

Huang, Emina H.; Johnson, Laura A.; Eaton, Kathryn A.; Hynes, Mark J.; Carpentino, Joseph E.; Higgins, Peter

doi:10.1007/s10620-010-1157-x

Cited by 19 publications

(12 citation statements)

References 22 publications

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“…Total cellular lysates were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) as previously described. 13 aSMA protein was detected with a mouse monoclonal antibody to human aSMA protein (Sigma). GAPDH protein expression was used as a loading control using a mouse antibody to GAPDH (Chemicon, Temecula, CA).…”

Section: Protein Expressionmentioning

confidence: 99%

Spironolactone and Colitis: Increased Mortality in Rodents and in Humans

Johnson

Govani

Joyce

et al. 2012

Inflammatory Bowel Diseases

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Background and Methods Crohn’s disease causes intestinal inflammation leading to intestinal fibrosis. Spironolactone is an anti-fibrotic medication commonly used in heart failure to reduce mortality. We examined whether spironolactone is anti-fibrotic in the context of intestinal inflammation. In vitro, spironolactone repressed fibrogenesis in TGFβ-stimulated human colonic myofibroblasts. However, spironolactone therapy significantly increased mortality in two rodent models of inflammation-induced intestinal fibrosis, suggesting spironolactone could be harmful during intestinal inflammation. Since IBD patients rarely receive spironolactone therapy, we examined whether spironolactone use was associated with mortality in a common cause of inflammatory colitis, Clostridium difficile infection (CDI). Results Spironolactone use during CDI infection was associated with increased mortality in a retrospective cohort of 4008 inpatients (15.9% vs. 9.1%, n=390 deaths, p<0.0001). In patients without liver disease, the adjusted OR for inpatient mortality associated with 80 mg spironolactone was 1.99 (95% CI: 1.51 – 2.63) In contrast to the main effect of spironolactone mortality, multivariable modeling revealed a protective interaction between liver disease and spironolactone dose. The adjusted odds ratio for mortality after CDI was 1.96 (95% CI: 1.50 – 2.55) for patients without liver disease on spironolactone vs. 1.28 (95% CI: 0.82 – 2.00) for patients with liver disease on spironolactone, when compared to a reference group without liver disease or spironolactone use. Conclusions We propose that discontinuation of spironolactone in patients without liver disease during CDI could reduce hospital mortality by 2-fold, potentially reducing mortality from CDI by 35,000 patients annually across Europe and the US.

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Section: Protein Expressionmentioning

confidence: 99%

Spironolactone and Colitis: Increased Mortality in Rodents and in Humans

Johnson

Govani

Joyce

et al. 2012

Inflammatory Bowel Diseases

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“…Various statins, which inhibit cholesterol synthesis by blocking activity of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR), have been shown to reduce tumor growth in xenograft models (Gao et al, 2010; Huang et al, 2010; Kochuparambil et al, 2011). Moreover, pharmacological inhibition of squalene synthase, the first committed step in cholesterol synthesis, lowered resistance to the chemotherapeutic agent doxorubicin in a xenograft model of liver cancer, albeit without significant effect on tumor growth, when used on its own (Montero et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Anticancer Activity of the Cholesterol Exporter ABCA1 Gene

2012

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Summary The ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I. Loss-of-function mutations in the ABCA1 gene induce Tangier disease and familial hypoalphalipoproteinemia, both cardio-vascular conditions characterized by abnormally low levels of serum cholesterol, increased cholesterol in macrophages and subsequent formation of vascular plaque. Increased intra-cellular cholesterol levels are also frequently found in cancer cells. Here we demonstrate anti-cancer activity of ABCA1 efflux function, which is compromised following inhibition of ABCA1 gene expression by oncogenic mutations or cancer-specific ABCA1 loss-of-function mutations. In concert with elevated cholesterol synthesis found in cancer cells, ABCA1 deficiency allows for increased mitochondrial cholesterol, inhibits release of mitochondrial cell death-promoting molecules and thus facilitates cancer cell survival, overall suggesting that elevated mitochondrial cholesterol is essential to the cancer phenotype.

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“…Statins are competitive small-molecule inhibitors of HMG-CoA reductase, and could prevent the transformation of HMG-CoA to mevalonate (24). Although in vitro data have suggested that ATST could suppress HCT116 cell growth and induce apoptosis, the effective doses of ATST in these experiments were relatively higher (50 and 100 µM, respectively) (12,25). In our experimental design, the maximum dose of ATST was only 25 µM.…”

Section: Discussionmentioning

confidence: 75%

Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

Zhou

Zheng

et al. 2017

Oncol Lett

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Abstract. Atorvastatin (ATST), a drug commonly used to reduce the levels of cholesterol and low-density lipoproteins, is a prospective agent for the prevention of colorectal cancer in patients with hyperlipidemia. ATST in combination with functional components is a promising strategy for cancer chemoprevention. In the present study, the growth inhibitory effect of ATST combined with phloretin (PT) on SW620 and HCT116 colon cancer cells was investigated. The results of MTT assays indicated that the combination of PT and ATST markedly reduced cell survival in both cell lines compared with PT or ATST treatment administered individually. The interaction indexes between PT and ATST, which were used to analyze their interaction pattern, were computed by the median-effect equation. The interaction indexes of each PT and ATST concentration pair were <1.0, which indicated a strong synergistic effect between the two compounds. The data obtained by flow cytometry and western blot analysis of cleaved-poly (ADP-ribose) polymerase indicated a synergistic effect resulted in apoptosis and cell cycle arrest at the G 2 /M checkpoint. Furthermore, combined treatment with PT and ATST markedly downregulated the expression of cyclin B and upregulated the expression of phospho-cdc2 and Myt1, which suggested that the activation of cdc2 was downregulated. This combined treatment strategy enhanced the anti-cancer activity of ATST at a relatively low dosage and suggested a possible method of preventing colorectal cancer in patients with hyperlipidemia.

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Atorvastatin Induces Apoptosis In Vitro and Slows Growth of Tumor Xenografts but Not Polyp Formation in Min Mice

Cited by 19 publications

References 22 publications

Spironolactone and Colitis: Increased Mortality in Rodents and in Humans

Spironolactone and Colitis: Increased Mortality in Rodents and in Humans

Anticancer Activity of the Cholesterol Exporter ABCA1 Gene

Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

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