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PubMed2002

Inhibition of proliferation and signalling mechanisms in human lymphocytes by fluvastatin.

1. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) reduce serum cholesterol and have proven benefits in the treatment of cardiovascular disease. However, recent work suggests that statins may exert immunosuppressive effects in isolated lymphocytes and in solid organ transplant recipients. Fluvastatin does not interfere with the metabolism of commonly used immunosuppressive agents and, therefore, may have benefits in transplant recipients. 2. The aim of the present study was to investigate the potential immunomodulatory effects of fluvastatin in vitro in human lymphocytes and the underlying effects on signal transduction. 3. In vitro, fluvastatin (10 micromol/L) caused a time-dependent inhibition of T cell proliferation in response to cross-linking of CD3. 4. Thymidine incorporation was reduced by 22, 81 and 92% at days 1, 3 and 5, respectively. 5. Mevalonate (1 micromol/L) treatment for 4 or 24 h significantly reduced the inhibitory effects of fluvastatin; the reversal was abrogated by simultaneous exposure to mevalonate and a farnesyl transferase inhibitor. 6. At a subcellular level, fluvastatin treatment was associated with reduced functional activity of Ras-dependent extracellular signal-regulated kinase pathways and of Rho-dependent p38 activation. 7. These data suggest that the potential immunosuppressive actions of statins involve inhibition of subcellular pathways dependent on isoprenylation of signal peptides, including Ras, Rho and related G-proteins.

Cell Division↗
PubMed1998

Cholesterol biosynthesis from lanosterol: differential inhibition of sterol delta 8-isomerase and other lanosterol-converting enzymes by tamoxifen.

The fact that administration of tamoxifen (Tam) to humans and laboratory animals (e.g., rats and monkeys) results in both a drastic reduction in cholesterol and a marked accumulation of certain sterol intermediates in their serum led us to undertake more direct biochemical studies on the mechanism of Tam's inhibitory action on the cholesterogenic enzymes. Of the five rat hepatic lanosterol-converting enzymes examined, the enzyme most sensitive to inhibition by Tam was sterol delta 8-isomerase (delta 8-SI) (a 208-fold inhibition relative to lanosterol 14 alpha-methyl demethylase), followed by sterol delta 24-reductase (13-fold) and sterol delta 14-reductase (5.2-fold). The inhibition patterns of all four affected enzymes were found to be noncompetitive, despite widely different inhibition constants (Ki) of 0.21 to 23.5 microM. The inhibitory activity of Tam on delta 8-SI was not affected by detergent-mediated solubilization of the microsomes. In Chinese hamster ovary cells, inhibition of delta 8-SI activity (IC50 = 0.15 microM) was paralleled by a decreased rate of [14C]-mevalonate incorporation into cholesterol (IC50 = 0.70 microM). Our results should provide more insight into an underlying mechanism of Tam's cardioprotective role by interfering the operation of the pathway of cholesterol biosynthesis from lanosterol in mammals.

Animals↗
PubMed1992

Regulation of intracellular actin polymerization by prenylated cellular proteins.

Posttranslational modification by covalent attachment of polyisoprene intermediates to a carboxyterminal CAAX-box motif is required for the biologic function of proteins such as p21ras, the supergene family of ras-related proteins, nuclear lamins, and subunits of heterotrimeric G-proteins. Cells grown in the presence of lovastatin, which inhibits HMG-CoA reductase and prevents synthesis of intermediates required for protein prenylation, develop a round, refractile morphology. Our data indicate that this is due to the selective loss of actin cables without gross changes in the microtubular lattice or intermediate filament structure. Microinjection of a competitive peptide inhibitor of protein prenyltransferases into the cytoplasm of cells induces an identical change in morphology with loss of actin cables. Mevalonate (MVA) reverses the lovastatin-induced morphologic change by inducing a rapid repolymerization of actin cables with coincident reversion to the flat morphology. Furthermore, microinjection of farnesyl-pyrophosphate or geranylgeranyl-pyrophosphate into lovastatin-treated cells also results in rapid morphologic reversion. The morphologic reversion induced by MVA requires the presence of serum, and is independent of extracellular calcium. The addition of cycloheximide to the growth medium prevents lovastatin-induced loss of actin cables, and causes morphologic reversion of lovastatin-treated cells by a mechanism that is independent of MVA. A1F4- induces morphologic reversion in a manner indistinguishable from MVA. These data indicate that prenylated protein(s) play a critical role in regulating the state of intracellular actin, and that GGPP can rescue the lovastatin-induced morphologic phenotype in the absence of upstream intermediates of cholesterol biosynthesis. We have begun to dissect the signaling events that mediate this pathway.

Actin Cytoskeleton↗
PubMed2000

Mitogenic effect of lithium in FRTL-5 cells can be reversed by blocking de novo cholesterol synthesis and subsequent signal transduction.

Lithium therapy is the therapeutic mainstay for bipolar disorder and has been associated in the thyroid with euthymic goiter, hyper and hypothyroidism as well as thyroid autoimmune disease. The FRTL-5 cell line is a well known model of thyroid cell physiology, where lithium has been shown to increase 3H-thymidine uptake at concentrations of 2 mM. This mitogenic effect was not associated with adenylate cyclase as measured by cyclic adenosine monophosphate (cAMP) production. The de novo synthesis of cholesterol is an important signal transduction pathway in FRTL-5 cells, where newly synthesized Rho GTPase is geranylgeranylated, enabling membrane localization of the G-protein and subsequent G1 to S-phase transition, resulting from extracellular stimulation. Here we confirm lithium mitogenicity at therapeutically relevant concentrations (1 mM) and demonstrate a lithium-associated accumulation of FRTL-5 cells in S-phase of the cell cycle. These effects could be abolished by Pravastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the rate-limiting enzyme in the formation of intermediates (de novo cholesterol synthesis) required for G-protein prenylation. Pravastatin, similar to lithium, showed no effect on cAMP production either under basal or thyroid stimulating hormone (TSH)-stimulated conditions indicating that de novo cholesterol synthesis is not involved with adenylate cyclase. The inhibitory effect of pravastatin could be overcome by reinitiating de novo cholesterol synthesis. This was achieved by the addition of the cell permeable, first metabolite (mevalonate) after HMG-CoA, which allowed the cycle to continue, leading eventually to protein prenylation, despite the presence of Pravastatin. These novel findings demonstrate lithium involvement in de novo cholesterol synthesis and G-protein prenylation, an important signal transduction pathway in FRTL-5 cells.

Animals↗
PubMed2004

Down-regulating effect of nicotine on connexin43 gap junctions in human umbilical vein endothelial cells is attenuated by statins.

We investigated the effect of nicotine on connexin43 (Cx43) expression and gap-junctional communication in human umbilical vein endothelial cells (HUVEC). We also evaluated whether the effect requires activation of acetyl choline receptors sensitive to nicotine (nAChRs) and is altered by statins. The results showed that expression of Cx43 protein is reduced by nicotine in a dose-dependent manner (6 x 10(-4) M nicotine vs control, 33% reduction, p < 0.01), though Cx43 mRNA is up-regulated (6 x 10(-4) M nicotine vs control, 36% increase, p < 0.01). Concomitantly, the communication function, determined by fluorescence recovery after photobleaching, is decreased (6 x 10(-4) M nicotine vs control, 38% reduction, p < 0.05). Such a down-regulation of Cx43 gap junctions by nicotine disappears in the presence of the nAChRs antagonist, dihydro-beta-erythroidine, and protease inhibitors leupeptin plus N-acetyl-Leu-Leu-Norleu-al (ALLN). Similarly, the effect of nicotine is attenuated by statins, including fluvastatin, lovastatin, pravastatin, and simvastatin, even at the presence of mevalonate. We concluded that i) nicotine down-regulates Cx43 expression and gap-junctional communication in HUVEC via post-transcriptional modification, which involves enhancement of Cx43 proteolysis; ii) the effect of nicotine is mediated via activation of nAChRs; and iii) the effect of nicotine is attenuated by statins through mechanisms outside the hypolipidemic pathway.

Cells, Cultured↗
PubMed1996

Leukotriene D4-induced mobilization of intracellular Ca2+ in epithelial cells is critically dependent on activation of the small GTP-binding protein Rho.

We have previously shown that the leukotriene D4 (LTD4)-induced mobilization of intracellular Ca2+ in epithelial cells is mediated by a G-protein that is distinctly different from the pertussis toxin-sensitive G-protein that regulates the subsequent influx of Ca2+. In the present study, we attempted to gain further knowledge about the mechanisms involved in the LTD4-induced mobilization of intracellular Ca2+ in epithelial cells by investigating the effects of compactin, an inhibitor of the isoprenylation pathway, on this signalling event. In cells preincubated with 10 microM compactin for 48 h, the LTD4-induced mobilization of intracellular Ca2+ was reduced by 75% in comparison with control cells. This reduction was reversed by co-administration of mevalonate (1 mM). The effect of compactin occurred regardless of whether or not Ca2+ was present in the extracellular medium, suggesting that isoprenylation must occur before Ca2+ is released from intracellular stores. In accordance with this, we also found that both the LTD4-induced formation of inositol 1,4,5-trisphosphate and the LTD4-induced phosphorylation of phospholipase C gamma 1 (PLC gamma 1) on tyrosine residues were significantly reduced in compactin-pretreated cells. These results open up the possibility that the activation of PLC gamma 1 is related to a molecule that is sensitive to impaired activity of the isoprenylation pathway, such as a small monomeric G-protein. This idea was supported by the observation that Clostridium botulinum C3 exoenzyme-induced inhibition of Rho proteins abolished the LTD4-induced intracellular mobilization of Ca2+. A regulatory role of Rho proteins in the LTD4-induced activation of PLC gamma 1 is unlikely to be indirectly mediated via an effect on the cytoskeleton, since cytochalasin D had no major effect on the LTD4-induced mobilization of Ca2+. Although the mechanism of interaction remains to be elucidated, the present findings indicate an important role of an isoprenylated protein such as Rho in the LTD4-induced Ca2+ signal.

ADP Ribose Transferases↗
PubMed1995

Simvastatin inhibits the cellular signaling and proliferative action of arginine vasopressin in cultured rat glomerular mesangial cells.

The present study was undertaken to determine whether an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, simvastatin, modulates the cellular action of arginine vasopressin (AVP) in the cultured rat glomerular mesangial cells. AVP increases cellular free calcium ([Ca2+]i) in a dose-dependent manner. The 1 x 10(-7) M AVP-mobilized [Ca2+]i was significantly reduced in the cells pretreated with 1 x 10(-6) M simvastatin. AVP produced a biphasic change in cellular pH, namely, an early acidification followed by a sustained alkalinization, and the AVP-induced cellular alkalinization disappeared after exposing to simvastatin. 1 x 10(-7) M AVP activated mitogen-activated protein (MAP) kinase from 15.5-30.4 pmol/mg protein, an effect significantly less in the presence of simvastatin. Also, 1 x 10(-7) M AVP significantly increased [3H]thymidine incorporation by 1.6-fold, and its incorporation was totally diminished in cells pretreated with simvastatin. The AVP-induced [Ca2+]i mobilization and MAP kinase activation were totally restored when cells were preexposed to a mixture of mevalonate and simvastatin. [3H]AVP receptor binding was not affected by the simvastatin treatment. 1 x 10(-7) AVP increased inositol trisphosphate production by 1.8-fold, which was significantly reduced by the presence of simvastatin. These results may indicate that nonsterol pathway plays a crucial role in the cellular action of AVP to produce cell growth of glomerular mesangium.

Animals↗
PubMed2002

Biosynthesis of nodulisporic acid A: precursor studies.

Nodulisporic acid A (NAA) is an indole-diterpene natural product produced by an indeterminate species of the endophytic fungus Nodulisporium. NAA (Figure 1) is structurally related to the paspaline class of fungal metabolites. The biosynthetic origin proposed for these alkaloids involves the acetate/mevalonic acid pathway leading to geranylgeranyl pyrophosphate (GGPP). GGPP is then proposed to condense with tryptophan to form the basic indole-diterpene core. A washed cell procedure was devised to incorporate labeled precursors into NAA by a mutant Nodulisporium culture designated MF6244. Incorporation of 2-(13)C-acetate and 2-(13)C-mevalonolactone into NAA was found to occur in the classical mevalonic acid pattern. In addition to the four mevalonic acid units that form the eastern side of the molecule, three additional isoprenylations occur to form the western and southern regions of NAA. Contrary to published reports on related compounds, incubations of Nodulisporium MF6244 with (14)C- and (13)C-tryptophan showed no incorporation of label into NAA. However, high levels of incorporation into NAA were obtained with known tryptophan precursors (14)C-, (13)C-, and (15)N-anthranilic acid and (14)C- and (13)C-ribose. A novel pathway for the biosynthesis of NAA is presented.

Acetates↗
PubMed1996

Target of cockroach allatostatin in the pathway of juvenile hormone biosynthesis.

Allatostatins, peptides with an YXFGL-amide C-terminus, cause a rapid and reversible inhibition of the sesquiterpenoid juvenile hormone III biosynthesis by cockroach corpora allata in vitro. Inhibition is relieved by farnesol and by mevalonate, and neither HMG-CoA reductase nor HMG-CoA synthesis (HMG-CoA synthase and acetoacetyl-CoA lyase) are inhibited by allatostatin. The neuropeptide is more effective as an inhibitor of JH III synthesis in glucose or amino acid-driven glands than in acetate-driven glands. Incorporation of label from acetate into JH III is increased whereas incorporation of label from glucose is decreased by allatostatin. Citrate is a very effective precursor for HMG-CoA synthesis in homogenates of corpora allata. We propose that inhibition of JH III biosynthesis by the tridecapeptide APSGAQRLYGFGL-amide occurs at the first committed step(s) of JH III synthesis, i.e. the transfer of 2C units from mitochondria to the cytoplasm by the tricarboxylate carrier and/or the ATP-citrate lyase.

Acetyl Coenzyme A↗
PubMed1997

Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase.

We have recently reported that the isoprenoid compound farnesol accelerates degradation of the cholesterologenic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, when added to cultured cells. We have thus proposed that farnesol is a required nonsterol regulator of this degradation event (T. E. Meigs, D. S. Roseman, and R. D. Simoni, 1996, J. Biol. Chem. 271, 7916-7922). In this report, we have studied the enzyme farnesyl pyrophosphatase (FPPase) in Chinese hamster ovary cells. We demonstrate that FPPase activity increases under conditions of increased metabolic flow through the isoprenoid pathway. Also, we show that a nonhydrolyzable analog of farnesyl pyrophosphate, an isoprenoid (phosphinylmethyl)phosphonate, inhibits FPPase in vitro, and when added to cells this inhibitor blocks the mevalonate-dependent, sterol-induced degradation of HMG-CoA reductase. Furthermore, exogenous farnesol overcomes the effect of this inhibitor. These results suggest an isoprenoid-mediated regulatory mechanism governing intracellular farnesol production and support the hypothesis that farnesol is a nonsterol regulator of reductase degradation.

Animals↗
PubMed2000

Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells.

Lovastatin, an HMG-CoA reductase inhibitor, was found to suppress growth and induce apoptosis in culture human promyelocytic leukaemic cell, HL-60. However, the mechanisms of lovastatin-induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin-induced apoptosis in HL-60 cells in a dose- and time-dependent manner. The features of this apoptosis were attenuated by the presence of mevalonate, a metabolic intermediate of cholesterol synthesis. Treatment of lovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase-3, but not caspase-1 activity. Lovastatin also stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP), and followed by the appearance of caspase activity and DNA fragmentation. Pretreatment with caspase-3 inhibitors, Ac-DEVD-CHO and Z-VAD-FMK, inhibited lovastatin induced caspase-3 activity and DNA fragmentation. Furthermore, we demonstrated that DNase II was involved in the DNA fragmentation induced by lovastatin. These results suggested that the mechanism of lovastatin induced HL-60 cells apoptosis through activation of caspase-3 and DNase II activities.

Apoptosis↗
PubMed1986

Mevalonate-5-diphosphate decarboxylase: stereochemical course of ATP-dependent phosphorylation of mevalonate 5-diphosphate.

Chicken liver mevalonate-5-diphosphate decarboxylase catalyzes the reaction of mevalonate 5-diphosphate (MVADP) with ATP to produce isopentenyl diphosphate, ADP, CO2, and inorganic phosphate. The overall reaction involves an anti elimination of the tertiary hydroxyl and carboxyl groups. To investigate the mechanism for transfer of the terminal phosphoryl group of ATP to the C-3 oxygen of MVADP, we have carried out the reaction using stereospecifically labeled (Sp)-adenosine 5'-O-(3-thio[3-17O2,18O]triphosphate) [( gamma-17O2,18O]ATP gamma S) in place of ATP. The configuration of the [17O,18O]thiophosphate produced was found to be Rp, corresponding to overall inversion of configuration at phosphorus in the thiophosphoryl group transfer step. This result is consistent with the direct transfer of the thiophosphoryl group from (Sp)-[gamma-17O2,18O]ATP gamma S to MVADP at the active site. Our result does not indicate the involvement of a covalent thiophosphoryl-enzyme on the reaction pathway.

Adenosine Triphosphate↗
PubMed1990

Plasma apolipoprotein E, high density lipoprotein1 (HDL1) and urinary mevalonate excretion in pancreatectomized diabetic dogs: effects of insulin and lovastatin.

Hypercholesterolemia and increased concentrations of an apolipoprotein E (apoE)-containing HDL subclass, high density lipoprotein1 (HDL1) have been observed in streptozocin-alloxan diabetic dogs consuming normal amounts of dietary cholesterol. The aim of this study was to characterize the response of HDL1 and its targeting ligand, apoE, to insulin and HMG-CoA reductase inhibitor treatment in pancreatectomized diabetic dogs. Following induction of diabetes, plasma total cholesterol, HDL1, and apoE concentrations were all increased. Urinary mevalonate excretion, an index of cholesterol synthesis in humans, was 6-fold that of nondiabetic controls. Lipoprotein fractionation by Pevikon block electrophoresis and gel filtration chromatography showed that the increased cholesterol and apoE were associated with alpha 2-migrating particles corresponding to HDL1. Insulin treatment, resulting in near normal fasting blood glucose concentrations in the group as a whole (average 5.1 mM, 92 mg/dl), led to variable reductions in apoE, total plasma cholesterol, and HDL1. Uncorrected dyslipidemia during intensified insulin treatment appeared to be related to failure to achieve euglycemia. Despite unremitting hyperglycemia, treatment with lovastatin resulted in pronounced decreases in plasma cholesterol, HDL1 and apoE to concentrations below those observed in nondiabetic animals. Mevalonate excretion also fell, but remained twice normal. Thus neither modality corrected all of the abnormalities in canine diabetic dyslipidemia. Since apoE-containing HDL1 may mediate cholesterol traffic between the periphery and the liver (reverse cholesterol transport), the present observations suggest that increased cholesterol synthesis is accompanied by parallel abnormalities in cholesterol flux through the reverse transport pathway in the canine model.

Animals↗
PubMed1990

Effects of CCl4 poisoning on metabolism of dolichol in rat liver microsomes and Golgi apparatus.

Carbon tetrachloride (CCl4) poisoning affects glycoprotein processing and maturation at the level of rat liver microsomes and Golgi apparatus. HPLC analysis showed that within 5-60 min after CCl4 administration the levels of total dolichol, free dolichol and dolichyl-phosphate strongly decreased both in total microsomes and in Golgi apparatus. The most marked and early reduction of total dolichol was observed in the secretory membranes of Golgi area already 15 min after CCl4 poisoning. The incubation of CCl4-pretreated isolated hepatocytes with [3H]-mevalonate showed a significant slowing down of the label incorporation into both free-dolichol and dolichyl-phosphate. Moreover, lipid peroxidation might cause alterations in the molecular structure of both free-dolichol and dolichyl-phosphate. A notable prevention of dolichol decrease was observed in animals pretreated with vitamin E. The results suggest that the prooxidant activity of CCl4 is able to affect the metabolism of dolichol either by increasing the oxidative degradation or impairing the biosynthetic pathway.

Animals↗
PubMed2000

Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells.

The effects of fluvastatin, a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) inhibitor, on the biosynthesis of tissue plasminogen activator (t-PA) and of its major physiological inhibitor (plasminogen activator inhibitor type 1, PAI-1) were investigated in cultured human umbilical vein endothelial cells (HUVEC). Fluvastatin (0.1 to 2.5 microM), concentration-dependently reduced the release of PAI-1 antigen by unstimulated HUVEC, subsequent to a reduction in PAI-1 steady-state mRNA levels and de novo protein synthesis. In contrast, it increased t-PA secretion. The drug also reduced PAI-1 antigen secreted in response to 10 microg/ml bacterial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor alpha (TNFalpha) or 0.1 microM phorbol myristate acetate (PMA). Mevalonate (100 microM), a precursor of isoprenoids, added to cells simultaneously with fluvastatin, suppressed the effect of the drug on PAI-1 both in unstimulated and stimulated cells as well as on t-PA antigen. Among intermediates of the isoprenoid pathway, all-transgeranylgeraniol (5 microM) but not farnesol (10 microM) prevented the effect of 2.5 microM fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synthesis is responsible for the observed effects.

Cells, Cultured↗
PubMed1999

Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer.

Pure and mixed isoprenoid end products of plant mevalonate metabolism trigger actions that suppress 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. These actions modulate HMG CoA reductase mRNA translation and the proteolytic degradation of HMG CoA reductase. Such post-transcriptional events, we propose, are activated directly by acyclic isoprenoids and indirectly by cyclic isoprenoids. Isoprenoids, acting secondarily to the dominant transcriptional effector of sterologenesis, modestly lower cholesterol levels, if and only if, sterologenesis is not repressed by a saturating imput of dietary cholesterol. An anomaly associated with tumor growth-a sterol feedback-resistant HMG CoA reductase activity-ensures a pool of sterologenic pathway intermediates. Such intermediates provide lipophilic anchors essential for membrane attachment and biological activity of growth hormone receptors, nuclear lamins A and B, and oncogenic ras. Tumor HMG CoA reductase retains high sensitivity to the isoprenoid-mediated secondary regulation. Repression of mevalonate synthesis by plant-derived isoprenoids reduces ras and lamin B processing, arrests cells in G1, and initiates cellular apoptosis. This unique tumor cell-specific sensitivity allows isoprenoids to be used for tumor therapy, an application emulating that of the statins, but one free of adverse effects. When evaluated at levels provided by a typical diet, isoprenoids individually have no impact on cholesterol synthesis and tumor growth. Nonetheless, isoprenoid-mediated activities are additive, and, sometimes synergistic. Therefore, the combined actions of the estimated 23,000 isoprenoid constituents of plant materials, acting in concert with other chemopreventive phytochemicals, may explain the lowered cancer risk associated with a diet rich in plant products. In contrast, that lowering of cancer risk does not correspond to supplemental intake of other dietary factors associated with fruits, vegetables, and cereal grains, namely fiber, beta-carotene, vitamin C, and vitamin E, and only weakly to supplemental folate.

Animals↗
PubMed2003

Natural products of the medicinal fungus Ganoderma lucidum: occurrence, biological activities, and pharmacological functions.

Ganoderma lucidum, a fungus used in traditional Chinese medicine, produces polysaccharides and oxygenated triterpenoids with a very broad spectrum of biological activities and pharmacological functions. Among the Ganoderma triterpenoids, many pairs of C-3 alpha/beta stereoisomers and C-3/C-15 positional isomers have been identified. Biosynthetic study has indicated that the C-3alpha series of oxygenated triterpenoids is derived from the C-3beta series via an oxidation-reduction pathway. The interaction of Ganoderma triterpenoids with human platelets in the induction of aggregation and inhibition of agonist-induced aggregation and signal transduction has been elucidated. Reduction of cellular mevalonate content to a stage in which cholesterol synthesis is strongly inhibited and cell growth is marginally arrested sensitizes hepatoma cells to the oxygenated triterpenoids. A combination treatment of lovastatin and Ganoderma triterpenoids in animal studies has exhibited a potential anticancer effect.

Animals↗
PubMed1995

Differential effects of monoterpenes and lovastatin on RAS processing.

Limonene and related monoterpenes have been shown to impair the incorporation of mevalonic acid-derived isoprene compounds, that is farnesyl pyrophosphate, into RAS and RAS-related proteins. As farnesylation is critical for RAS's membrane localization and function, the isoprenylation pathways have received attention as potential targets of anti-RAS pharmacologic maneuvers. We have expanded on these prior studies and demonstrate that one of limonene's metabolic derivatives, perillyl alcohol, decreases the levels of antigenic RAS in the human-derived myeloid THP-1 and lymphoid RPMI-8402 cell lines. Both limonene and perillyl alcohol decrease levels of [35S]methionine-labeled RAS proteins in cells that have been pulsed with radiolabeled methionine for 4 h. In contrast, lovastatin, which inhibits hydroxymethylglutaryl coenzyme A reductase and thus depletes cells of farnesyl pyrophosphate, does not diminish levels of total antigenic RAS but rather results in a shift in the RAS protein; levels of farnesylated RAS decrease whereas levels of unmodified/unfarnesylated RAS increase. As limonene and perillyl alcohol do not induce such a shift, we conclude that these monoterpenes decrease farnesylated RAS protein levels by a mechanism that is clearly distinct from that of either depleting cells of farnesyl pyrophosphate or inhibiting the enzyme farnesyl protein transferase that catalyzes the post-translational farnesylation of RAS. Perillyl alcohol decreases antigenic RAS levels but does not decrease levels of another membrane-tethered protein, the alpha subunit of the heterotrimeric G protein. Furthermore, perillyl alcohol decreases the levels of radiolabeled methionine incorporated into immunoprecipitable RAS to a greater extent than it decreases radiolabeled methionine incorporated into total cellular protein. Thus there is some degree of specificity for the activity of perillyl alcohol to depress RAS levels.

Cells, Cultured↗