Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Maltese, William A.; Defendini, Richard; Green, R A; Sheridan, Kathleen; Donley, Dustin K.

doi:10.1172/jci112165

Cited by 115 publications

(47 citation statements)

References 47 publications

(27 reference statements)

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“…Recently, Morris et al (1995) found that lovastatin slows growth of hepatoma tissue culture-4 (HTC-4) cells at low concentrations. Lovastatin also slows cell growth in vivo (Maltese et al, 1985). Sumi et al (1992) observed that growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice is inhibited by s.c. injection of lovastatin.…”

Section: Discussionmentioning

confidence: 99%

Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats

Tatsuta

Baba²,

Iseki³

et al. 1998

Br J Cancer

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Summary The effect of pravastatin, an inhibitor of p21 ras isoprenylation, on hepatocarcinogenesis induced by N-nitrosomorpholine and on p2l s isoprenylation were investigated in male Sprague-Dawley rats. Rats received i.p. injections of pravastatin (10 and 20 mg kg-1 body weight) every other day and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Vesible white nodules and hepatic lesions staining positively for gamma-glutamyl transpeptidase or glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 15, pravastatin at both dosages significantly reduced the incidence, number and volume of visible white nodules. Quantitative histological analysis also showed that prolonged administration of pravastatin at both dosages resulted in significant reductions in the number and percentage area of hepatic lesions positive for gamma-glutamyl transpeptidase and glutathione-S-transferase, placental type. Administration of pravastatin also significantly decreased the amount of membrane-associated p21 ras in the tumour and the labelling index of neoplastic nodules and increased the apoptoic indices of neoplastic nodules. These findings indicate that pravastatin suppresses hepatocarcinogenesis and suggest that this effect might be related to pravastatin's inhibition of p21 ras isoprenylation and its subsequent inhibition of cell proliferation and induction of apoptosis in neoplastic lesions.

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Section: Discussionmentioning

confidence: 99%

Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats

Tatsuta

Baba²,

Iseki³

et al. 1998

Br J Cancer

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“…6,7 Statins are competitive inhibitors of 3-hydroxy-3 methylglutarylcoenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate-to-cholesterol biosynthesis pathway. These drugs effectively lower circulating cholesterol levels by decreasing the intracellular synthesis of cholesterol, predominantly in the liver.…”

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confidence: 99%

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Moriceau

Roelofs

Brion

et al. 2011

Cancer

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BACKGROUND: Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis. METHODS: The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines. RESULTS: Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used. CONCLUSIONS: The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma. Cancer 2012;118:750-

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“…Mevalonic acid, produced by HMG-CoA reductase, regulates cell growth independent of cholesterogenesis: Ras p21 and lamins A and B undergo covalent modification at the carboxyl terminus by mevalonate-derived farnesyl isoprenoid (Goldstein and Brown, 1990). HMG-CoA reductase inhibitors exhibit cytostatic activity possibly as signal transduction inhibitors, when added to proliferating cells in culture or in vivo (Goldstein et al, 1979;Habenicht et al, 1980;Maltese et al, 1985). Decreased farnesyl isoprenoid formation by these inhibitors could lead to suppression of tumour growth by interfering with the function of Ras p21.…”

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confidence: 99%

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

et al. 2001

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Summary Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg -1 d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment.

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Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Cited by 115 publications

References 47 publications

Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats

Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

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