Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells

Degraeve, F.; Bolla, Manlio; Blaie, Stéphanie; Créminon, Christophe; Quéré, Isabelle; Boquet, Patrice; Lévy-Toledano, S; Bertoglio, Jacques; Habib, Aı̈da

doi:10.1074/jbc.m104197200

Cited by 94 publications

(60 citation statements)

References 69 publications

(66 reference statements)

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“…We observed both phenomena. In addition, although others (31,32) have shown higher concentrations (10 or 20 Amol/L) of lovastatin and simvastatin induced COX-2 protein expression in various cell lines, our data showed that a low concentration (2 Amol/L) of lovastatin and simvastatin also induced COX-2 expression in prostate cancer cell lines. Moreover, our data suggested that inactivation of RhoA may be the molecular mechanism by which statin mediates its antitumor activity.…”

Section: Discussionmentioning

confidence: 60%

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

Hoque

Chen

Xu³

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

183

136

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Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase -mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G 1 phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G 1 cell cycle. Future studies should focus on examining statins and other apoptosisinducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):88 -94)

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Section: Discussionmentioning

confidence: 60%

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

Hoque

Chen

Xu³

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

183

136

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“…Cyclooxygenase-2 (COX-2) overexpression in MDA-MB-231 breast cancer cells causes an increase production of IL-8 (24). GGTI-286, a selective inhibitor of geranylgeranyltransferases, increases COX-2 expression in smooth muscle cells (25). It is therefore possible that NE-10790 stimulates COX-2 expression in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth InhibitionIn vivo

et al. 2008

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Bisphosphonates bind avidly to bone mineral and are potent inhibitors of osteoclast-mediated bone destruction. They also exhibit antitumor activity in vitro. Here, we used a mouse model of human breast cancer bone metastasis to examine the effects of risedronate and NE-10790, a phosphonocarboxylate analogue of the bisphosphonate risedronate, on osteolysis and tumor growth. Osteolysis was measured by radiography and histomorphometry. Tumor burden was measured by fluorescence imaging and histomorphometry. NE-10790 had a 70-fold lower bone mineral affinity compared with risedronate. It was 7-fold and 8,800-fold less potent than risedronate at reducing, respectively, breast cancer cell viability in vitro and bone loss in ovariectomized animals. We next showed that risedronate given at a low dosage in animals bearing human B02-GFP breast tumors reduced osteolysis by inhibiting bone resorption, whereas therapy with higher doses also inhibited skeletal tumor burden. Conversely, therapy with NE-10790 substantially reduced skeletal tumor growth at a dosage that did not inhibit osteolysis, a higher dosage being able to also reduce bone destruction. The in vivo antitumor activity of NE-10790 was restricted to bone because it did not inhibit the growth of subcutaneous B02-GFP tumor xenografts nor the formation of B16-F10 melanoma lung metastases. Moreover, NE-10790, in combination with risedronate, reduced both osteolysis and skeletal tumor burden, whereas NE-10790 or risedronate alone only decreased either tumor burden or osteolysis, respectively.In conclusion, our study shows that decreasing the bone mineral affinity of bisphosphonates is an effective therapeutic strategy to inhibit skeletal tumor growth in vivo. [Cancer Res 2008;68(21):8945-53]

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“…Statins are also known for their pleiotropic effects, which are independent of their lipid-lowering properties (4). Among the effects of statins, the most relevant are anti-atherosclerotic (5) and anti-inflammatory actions (6), improvement of endothelial dysfunction (7), anti-thrombosis (8) and anti-oxidant (9) actions, prevention of Alzheimer's disease (10), and antineoplasic actions (3).…”

Section: Introductionmentioning

confidence: 99%

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

Gonçalves

Calou

Siqueira

et al. 2011

Braz J Med Biol Res

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Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid-lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g) and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20-25 g), which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan), at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively). Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation) reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively) and second phase (73, 57, and 66% inhibition of licking time, respectively). The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc). Lovastatin (0.01, 0.1, and 1 µg/mL) inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils) infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-α (TNF-α) and the inducible form of nitric oxide synthase (iNOS) activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin.

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Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells

Cited by 94 publications

References 69 publications

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

Statin Induces Apoptosis and Cell Growth Arrest in Prostate Cancer Cells

Lowering Bone Mineral Affinity of Bisphosphonates as a Therapeutic Strategy to Optimize Skeletal Tumor Growth InhibitionIn vivo

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

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