Mevastatin

The Penicillium Citrinum

Mevastatin is an inhibitor of HMG-CoA reductase with Ki value of 1nM [1].

Mevastatin inhibits HMG-CoA reductase reversibly and competes with HMG-CoA. It shows a Ki value of about 1nM. Mevastatin inhibits sterol synthesis from acetate in various cells at low concentration of nanomolar. It also inhibits acetate incorporation with IC50 value of 1nM. Besides that, mevastatin completely suppresses the growth of L cells at 1.3μM. Mevastatin is also found to affect the cell cycle and change cell morphology in cultured fibroblasts [1].

In rats, administration of mevastatin inhibits sterol synthesis in the liver and reduces plasma cholesterol levels. In patients with familial hypercholesterolemia, mevastatin also shows potent effects on reducing plasma cholesterol. Mevastatin at dose of 50 mg/day reduces 25% total cholesterol in a FH heterozygote patient treated with 2 months [1].

References:
[1] Endo A. The discovery and development of HMG-CoA reductase inhibitors. Journal of lipid research, 1992, 33(11): 1569-1582.

Activation of c-Jun N-terminal kinase is required for mevastatin-induced apoptosis of salivary adenoid cystic carcinoma cells.[Pubmed:20629200]

Anticancer Drugs. 2010 Aug;21(7):678-86.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, originally developed for lowering cholesterol. Statins also have pleiotropic effects, independent of cholesterol-lowering effects, including induction of apoptosis in various cell lines. However, the mechanism underlying statin-induced apoptosis is still not fully understood. This study aims to explore the proapoptotic effects and underlying mechanisms of statins on human salivary adenoid cystic carcinoma (SACC). Exposure of SACC cells to Mevastatin resulted in cell growth inhibition and apoptosis in a dose-dependent manner, accompanied by the release of cytochrome c and cleavage of caspase-3. A remarkable decrease in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and increase in phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase were observed. Furthermore, the JNK-specific inhibitor SP600125, but not the p38-specific inhibitor SB203580, abolished Mevastatin-induced cell growth inhibition and apoptosis in SACC cells. This was supported by results in which the JNK inhibitor efficiently blocked Mevastatin-induced JNK phosphorylation, but not p38 phosphorylation, and further decreased Mevastatin-induced phosphorylation of ERK1/2. Taken together, the results suggest that the JNK pathway was required for Mevastatin-induced cell growth inhibition and apoptosis in SACC cells. Statins could be potential anticancer agents for SACC chemotherapy.

Mevastatin-induced neurite outgrowth of neuroblastoma cells via activation of EGFR.[Pubmed:19224573]

J Neurosci Res. 2009 Jul;87(9):2138-44.

Neuroblastoma cell lines are commonly used as models to study neuronal differentiation, as they retain the capacity to differentiate into a neuronal-like phenotype. Receptor tyrosine kinase (RTK) signaling is essential for neuronal differentiation during development, and cholesterol-containing lipid-rafts are important for RTK signaling. Hydroxymethylglutaryl-coenzyme A reductase inhibitors of the statin family impair cholesterol biosynthesis and are in widespread clinical use for the treatment of cardiovascular diseases. It is of great clinical interest that statin treatment also correlates with a lower incidence of malignancies. We found that Mevastatin triggered neurite outgrowth of neuroblastoma cells and examined the responsible signaling pathways. Treatment of Neuro2a cells with Mevastatin for 24 hr induced neurite outgrowth associated with up-regulation of the neuronal marker protein NeuN. Interestingly, we found that Mevastatin triggered phosphorylation of the key kinases epidermal growth factor receptor (EGFR), ERK1/2, and Akt/protein kinase B. Inhibition of EGFR, PI3K, and the mitogen-activated protein kinase cascade blocked Mevastatin-induced neurite outgrowth. Moreover, add-back experiments of cell-permeable cholesterol precursors indicated that farnesylated and geranylgeranylated proteins play a major role in statin-induced neurite outgrowth. Taken together, our results provide the first mechanistic insight into statin-triggered signaling pathways that lead to neurite outgrowth in neuroblastoma cells. Surprisingly, we revealed that Mevastatin triggered the phosphorylation of the EGFR and that this was because of the inhibition of farnesylated and geranylgeranylated proteins. We propose that members of the large family of farnesylated or geranylgeranylated small GTPases (such as Rabs or Rap1) regulating the trafficking and signaling of EGFR might be responsible for the statin-induced effects on EGFR signaling.

[Mevastatin inhibits the differentiation of thyroid-associated ophthalmopathy derived orbital preadipocytes].[Pubmed:20543477]

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010 May;35(5):511-7.

OBJECTIVE: To investigate the effect of Mevastatin (Mev) on the expression of peroxisome-proliferator-activated receptor-gamma (PPAR-gamma) mRNA and differentiation of Thyroid-associated ophthalmopathy (TAO) derived orbital preadipocytes in vitro. METHODS: Orbital adipose tissues were obtained from TAO patients undergoing orbital decompression surgery. The orbital preadipocytes cultured from the orbital adipose tissues were divided into Group A (a control group) and Group B (an intervention group). Group B was subdivided into Group B1-B5, all groups were stimulated to differentiate into mature adipocytes with cocktail differentiation medium.The entire course of differentiation was 10 d. The differentiation of orbital preadipocytes in Group A was induced with routine inducer,while at in Group B1,B2, and B3 was interfered with 5 micromol/L (B1), 10 micromol/L(B2),20 micromol/L (B3) Mevastatin respectively during the whole process of differentiation. The differentiation of orbital preadipocytes in Group B4 and B5 was interfered with 10 micromol/L Mevastatin day 4 (B4) or day 8 (B5) of the differentiation process until the entire course was over. Intracellular fat accumulation in differentiated adipocytes was determined by oil red O staining. The value of optical absorption was measured at 492 nm with enzyme-linked immunosorbent assay. The expression of PPAR-gamma mRNA was detected by reverse transcription polymerase chain reaction. RESULTS: The light absorption value (A) and PPAR-gamma mRNA expression of differentiated cells in Group A,B1,B2,and B3 decreased successively,and there was significant difference in any of the 2 groups among Group A, B1 and B2, and B3 (P<0.05). The value A and PPAR-gamma mRNA expression of differentiated cells in Group A, B4, and B2 decreased successively, and the difference in any of the 2 groups among these 3 groups was significant. However, there were no significant difference between Group A and B5. CONCLUSION: Mevastatin inhibits the differentiation of TAO derived orbital preadipocytes by blocking PPAR-gamma mRNA expression. The degree of inhibition is not only concentration-dependent but also associated with the stage of differentiation. The earlier the differentiation, the stronger the inhibition.

Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice.[Pubmed:11283400]

Stroke. 2001 Apr;32(4):980-6.

BACKGROUND AND PURPOSE: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) lower serum cholesterol and decrease the incidence of stroke and cardiovascular disease. There is growing evidence that statins exert some of their beneficial effects independent of cholesterol lowering. Indeed, we have previously demonstrated that chronic simvastatin administration upregulates endothelial nitric oxide synthase (eNOS), resulting in more functional protein, augmentation of cerebral blood flow, and neuroprotection in a murine model of cerebral ischemia. In this report we examined whether another member of the statin family shared these effects and whether eNOS upregulation is sustained with longer treatment. METHODS: Mevastatin (2 mg/kg or 20 mg/kg per day) was administered to 18- to 22-g male mice for 7, 14, or 28 days before 2-hour middle cerebral artery occlusion with the use of the filament model (n=9 to 12). Neurological deficits and cerebral infarct volumes were assessed at 24 hours. Arterial blood pressure and gases, relative cerebral blood flow, and blood cholesterol levels were monitored in a subset of animals (n=5). Absolute cerebral blood flow was measured by the [(14)C]iodoamphetamine indicator fractionation technique (n=6). eNOS mRNA and protein levels were determined. RESULTS: Mevastatin increased levels of eNOS mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. Greatest protection was seen with 14- and 28-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced only after 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment. CONCLUSIONS: Chronic prophylactic treatment with Mevastatin upregulated eNOS and augmented cerebral blood flow. These changes occurred in the absence of changes in serum cholesterol levels, were sustained for up to 1 month of treatment, and resulted in neuroprotection after middle cerebral artery occlusion.

HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2.[Pubmed:11408350]

Carcinogenesis. 2001 Jul;22(7):1061-7.

Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Butyrate, a short-chain fatty acid, reduces proliferation and induces differentiation of human colon cancer cells. The aim of our study was to determine the effect of Mevastatin, alone or in combination with butyrate, on proliferation, the cell cycle and apoptosis in the human colorectal carcinoma cell line Caco-2. In this report we show that Mevastatin combined with butyrate synergistically suppressed growth of Caco-2 cells in a dose- and time-dependent manner. In addition, incubation with Mevastatin arrested cells in the G1 phase of the cell cycle after 24 h with a switch to the G2/M phase after 72 h. This was accompanied by a down-regulation of cyclin-dependent kinases (cdk) 4 and cdk 6 as well as cyclin D1, while cdk 2 and cyclin E protein levels remained unchanged during Mevastatin treatment. Cell cycle inhibitors p21 and p27 were significantly upregulated by Mevastatin. The proapoptotic properties of Mevastatin were further enhanced by co-incubation with butyrate. Lastly, the effects of Mevastatin could be reversed by addition of mevalonate, but not farnesyl- or geranylgeranylpyrophosphate, intermediate products of cholesterol synthesis, to the medium. These results suggest that HMG-CoA reductase inhibitors like Mevastatin may enhance the antiproliferative effect of butyrate in colon cancer cells via induction of apoptosis together with a G0/G1 cell cycle arrest.

Effects of compactin, mevalonate and low-density lipoprotein on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and low-density-lipoprotein-receptor activity in the human hepatoma cell line Hep G2.[Pubmed:6089762]

Biochem J. 1984 Aug 15;222(1):35-9.

Compactin, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase, decreased cholesterol synthesis in intact Hep G2 cells. However, after the inhibitor was washed away, the HMG-CoA-reductase activity determined in the cell homogenate was found to be increased. Also the high-affinity association of LDL (low-density lipoprotein) to Hep G2 cells was elevated after incubation with compactin. Lipoprotein-depleted serum, present in the incubation medium, potentiated the compactin effect compared with incubation in the presence of human serum albumin. Addition of either mevalonate or LDL prevented the compactin-induced rise in activities of both HMG-CoA reductase and LDL receptor in a comparable manner. It is concluded that in this human hepatoma cell line, as in non-transformed cells, both endogenous mevalonate or mevalonate-derived products and exogenous cholesterol are able to modulate the HMG-CoA reductase activity as well as the LDL-receptor activity.

Mevastatin (Compactin) is a first HMG-CoA reductase inhibitor that belongs to the statins class. Mevastatin is a lipid-lowering agent, and induces apoptosis, arrests cancer cells in G0/G1 phase. Mevastatin also increases endothelial nitric oxide synthase (eNOS) mRNA and protein levels. Mevastatin has antitumor activity and has the potential for cardiovascular diseases treatment.

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