Effects of HMG-CoA reductase inhibitors on growth and differentiation of cultured rat skeletal muscle cells

Veerkamp, J.H.; Smit, Johannes W. A.; Benders, A.A.G.M.; Oosterhof, Arie

doi:10.1016/0925-4439(95)00122-0

Cited by 16 publications

(7 citation statements)

References 45 publications

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“…Therefore, the clinical use of statins may be characterized by the occurrence of adverse effects, such as rhabdomiolysis and peripheral neuropathy (Corsini et al, 1995;Phan et al, 1995;Veerkamp et al, 1996). On the contrary, manumycin is a specific FPTase inhibitor that does not affect the biosynthesis of end products of isoprenoid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

et al. 2000

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SummaryThe aim of the present study was to assess the cytotoxicity of manumycin, a specific inhibitor of farnesyl:protein transferase, as well as its effects on protein isoprenylation and kinase-dependent signal transduction in COLO320-DM human colon adenocarcinoma which harbours a wild-type K-ras gene. Immunoblot analysis of isolated cell membranes and total cellular lysates of COLO320-DM cells demonstrated that manumycin dose-dependently reduced p21ras farnesylation with a 50% inhibitory concentration (IC 50 ) of 2.51 ± 0.11 µM and 2.68 ± 0.20 µM, respectively, while the geranylgeranylation of p21rhoA and p21rap1 was not affected. Manumycin dose-dependently inhibited (IC 50 = 2.40 ± 0.67 µM) the phosphorylation of the mitogen-activated protein kinase/extracellular-regulated kinase 2 (p42MAPK/ERK2), the main cytoplasmic effector of p21ras, as well as COLO320-DM cell growth (IC 50 = 3.58 ± 0.27 µM) without affecting the biosynthesis of cholesterol. Mevalonic acid (MVA, 100 µM), a substrate of the isoprenoid synthesis, was unable to protect COLO320-DM cells from manumycin cytotoxicity. Finally, manumycin 1-25 µM for 24-72 h induced oligonucleosomal fragmentation in a dose-and timedependent manner and MVA did not protect COLO320-DM cells from undergoing DNA cleavage. The present findings indicate that the inhibition of p21ras processing and signal transduction by manumycin is associated with marked inhibition of cell proliferation and apoptosis in colon cancer cells and the effect on cell growth does not require the presence of a mutated ras gene for maximal expression of chemotherapeutic activity.

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Section: Discussionmentioning

confidence: 99%

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

et al. 2000

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“…Other studies highlight properties of lovastatin that seem unrelated to cholesterol biosynthesis. For example, treatment of cells with the lovastatin analogue, simvastatin (more potent than lovastatin) resulted in regeneration of cultured rat skeletal muscle cells with a toxic effect on growth and differentiation, without influencing the cholesterol and phospholipid content of the cells (34). Inhibition of the HMG-CoA reductase also induces differentiation of human monocytic cells associated with growth retardation and expression of differentiation markers (35).…”

Section: Discussionmentioning

confidence: 99%

Lovastatin-mediated G ₁ arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase

Rao

Porter

Chen

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

334

233

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In this paper we present the finding that lovastatin arrests cells by inhibiting the proteasome, which results in the accumulation of p21 and p27, leading to G 1 arrest. Lovastatin is an inhibitor of hydroxymethyl glutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Previously, we reported that lovastatin can be used to arrest cultured cells in the G 1 phase of the cell cycle, resulting in the stabilization of the cyclin-dependent kinase inhibitors (CKIs) p21 and p27. In this report we show that this stabilization of p21 and p27 may be the result of a previously unknown function of the pro-drug, ␤-lactone ring form of lovastatin to inhibit the proteasome degradation of these CKIs. The lovastatin mixture used in this study is 80% open-ring form and 20% pro-drug, ␤-lactone form. We show that while the lovastatin open-ring form and pravastatin (a lovastatin analogue, 100% open ring) inhibit the HMG-CoA reductase enzyme, lovastatin pro-drug inhibits the proteasome but does not inhibit HMG-CoA reductase. In addition, many of the properties of proteasome inhibition by the prodrug are the same as the specific proteasome inhibitor lactacystin. Lastly, mevalonate (used to rescue cells from lovastatin arrest) unexpectedly abrogates the lactacystin and lovastatin pro-drug inhibition of the proteasome. Mevalonate increases the activity of the proteasome, which results in degradation of the CKIs, allowing lovastatin-and lactacystinarrested cells to resume cell division. The lovastatin-mediated inhibition of the proteasome suggests a unique mechanism for the chemopreventative effects of this agent seen in human cancer.

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“…These studies suggested that the depletion of GGPP is the root cause of cell death induced by statins. In rat skeletal myoblasts, however, statins induce cell death and inhibit differentiation at low doses, which do not affect the synthesis of cholesterol, and the statin-induced effects are not abolished by mevalonate (Veerkamp et al, 1996). The mechanism of the effect of statins at low doses is still unclear.…”

Section: Introductionmentioning

confidence: 95%

SIMVASTATIN REDUCES INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN DIFFERENTIATING C2C12 MOUSE MYOBLAST CELLS IN AN HMG-CoA REDUCTASE INHIBITION-INDEPENDENT MANNER

Ogura¹,

Tanaka²,

Nakata³

et al. 2007

J. Toxicol. Sci.

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-Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase occasionally cause myopathy characterized by weakness, pain, and elevated serum creatine phosphokinase (CK). In this study, we investigated the effects of simvastatin, an HMG-CoA reductase inhibitor, on the viability and insulin-like growth factor-1 (IGF-1) signaling in differentiating C2C12 mouse myoblast cells. Simvastatin decreased cell viability and CK activity, a marker of myogenesis, in differentiating cells in a dosedependent manner. Although the simvastatin-induced decrease in viability in proliferating and differentiated cells was completely abolished by mevalonate or geranylgeranyl-pyrophosphate, the inhibitory effects of simvastatin in differentiating cells were not abolished by mevalonate or isoprenoid derivatives of mevalonate. Moreover, the sensitivity of differentiating cells to simvastatin regarding cell viability was about 7 times higher than that of proliferating cells. After induction of differentiation in the presence of 1 μM simvastatin for 2 days, IGF-1-induced activation of ERK1/2 and Akt was significantly decreased. Although mRNA expression of the IGF-1 receptor β-chain (IGF-1Rβ) did not change, protein level of the 200 kDa IGF-1Rβ precursor was significantly increased by simvastatin in a dose-dependent manner. Mevalonate did not abolish the effect of simvastatin on IGF-1Rβ expression. These results suggest that simvastatin decreases IGF-1 signaling via a regulation of the post-translational modification of IGF-1Rβ in an HMG-CoA reductase inhibition-independent manner.

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Effects of HMG-CoA reductase inhibitors on growth and differentiation of cultured rat skeletal muscle cells

Cited by 16 publications

References 45 publications

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

Lovastatin-mediated G ₁ arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase

SIMVASTATIN REDUCES INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN DIFFERENTIATING C2C12 MOUSE MYOBLAST CELLS IN AN HMG-CoA REDUCTASE INHIBITION-INDEPENDENT MANNER

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Effects of HMG-CoA reductase inhibitors on growth and differentiation of cultured rat skeletal muscle cells

Cited by 16 publications

References 45 publications

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

Lovastatin-mediated G 1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase

SIMVASTATIN REDUCES INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN DIFFERENTIATING C2C12 MOUSE MYOBLAST CELLS IN AN HMG-CoA REDUCTASE INHIBITION-INDEPENDENT MANNER

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Lovastatin-mediated G ₁ arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase