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      Rosuvastatin Counteracts Vessel Arterialisation and Sinusoid Capillarisation, Reduces Tumour Growth, and Prolongs Survival in Murine Hepatocellular Carcinoma

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          Abstract

          Background and Aims. An arterial blood supply and phenotypic changes of the sinusoids characterise the liver vasculature in human hepatocellular carcinoma (HCC). We investigated the effects of rosuvastatin on liver vessel anomalies, tumour growth and survival in HCC. Methods. We treated transgenic mice developing HCC, characterized by vessel anomalies similar to those of human HCC, with rosuvastatin. Results. In the rosuvastatin group, the survival time was longer ( P < .001), and liver weight ( P < .01) and nodule surface ( P < .01) were reduced. Rosuvastatin decreased the number of smooth muscle actin-positive arteries ( P < .05) and prevented the sinusoid anomalies, with decreased laminin expression ( P < .001), activated hepatic stellate cells ( P < .001), and active Notch4 expression. Furthermore, rosuvastatin inhibited endothelial cell but not tumour hepatocyte functions. Conclusions. Rosuvastatin reduced the vessel anomalies and tumour growth and prolonged survival in HCC. These results represent new mechanisms of the effects of statin on tumour angiogenesis and a potential target therapy in HCC.

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          Statins and cancer prevention.

          Marie-France Demierre, Peter Higgins, Stephen B. Gruber … (2005)
          Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.
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            Statins have biphasic effects on angiogenesis.

            Michael C. Weis, Christopher Heeschen, John P Cooke … (2002)
            Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model. HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.
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              Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma.

              Albert Morales, Jesus Prieto-Lloret, Josep M Lluis … (2008)
              Cholesterol metabolism is deregulated in carcinogenesis, and cancer cells exhibit enhanced mitochondrial cholesterol content whose role in cell death susceptibility and cancer therapy has not been investigated. Here, we describe that mitochondria from rat or human hepatocellular carcinoma (HC) cells (HCC) or primary tumors from patients with HC exhibit increased mitochondrial cholesterol levels. HCC sensitivity to chemotherapy acting via mitochondria is enhanced upon cholesterol depletion by inhibition of hydroxymethylglutaryl-CoA reductase or squalene synthase (SS), which catalyzes the first committed step in cholesterol biosynthesis. HCC transfection with siRNA targeting the steroidogenic acute regulatory protein StAR, a mitochondrial cholesterol-transporting polypeptide which is overexpressed in HCC compared with rat and human liver, sensitized HCC to chemotherapy. Isolated mitochondria from HCC with increased cholesterol levels were resistant to mitochondrial membrane permeabilization and release of cytochrome c or Smac/DIABLO in response to various stimuli including active Bax. Similar behavior was observed in cholesterol-enriched mitochondria or liposomes and reversed by restoring mitochondrial membrane order or cholesterol extraction. Moreover, atorvastatin or the SS inhibitor YM-53601 potentiated doxorubicin-mediated HCC growth arrest and cell death in vivo. Thus, mitochondrial cholesterol contributes to chemotherapy resistance by increasing membrane order, emerging as a novel therapeutic niche in cancer therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Gastroenterol Res Pract
                Journal ID (publisher-id): GRP
                Title: Gastroenterology Research and Practice
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1687-6121
                ISSN (Electronic): 1687-630X
                Publication date (Print): 2010
                Publication date (Electronic): 22 February 2011
                Volume: 2010
                Electronic Location Identifier: 640797
                Affiliations
                1Institut des Vaisseaux et du Sang, Hôpitlal Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
                2“Angiogenèse et Recherche Translationnelle” INSERM U 965 “Equipe labellisée Ligue 2009”, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
                3Université Paris 7 Denis Diderot, 10 Avenue de Verdun, 75010 Paris, France
                4Laboratoire M.E.R.C.I, Université de Rouen, 22 Boulevard Gambetta, 76183 Rouen Cedx, France
                5Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
                6Paris Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France
                7Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France
                8Université Descartes-Paris 5, 12 Rue de l'École de Médecine, 75006 Paris, France
                Author notes

                Academic Editor: Fabio Marra

                Article
                DOI: 10.1155/2010/640797
                PMC ID: 3082163
                PubMed ID: 21528105
                SO-VID: 84e87aa5-585d-457e-acf7-cb1e8aeeee11
                Copyright © Copyright © 2010 Annemilaï Tijeras-Raballand et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 29 September 2010
                Date accepted : 28 December 2010
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Gastroenterology & Hepatology
                Data availability:
                ScienceOpen disciplines: Gastroenterology & Hepatology

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