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PubMed2005

Enhanced pathogenicity of Candida albicans pre-treated with subinhibitory concentrations of fluconazole in a mouse model of disseminated candidiasis.

OBJECTIVES: To investigate the relative pathogenicity of Candida albicans treated with subinhibitory concentrations of fluconazole in a mouse model of disseminated candidiasis. Previous studies indicate that these cells secrete 10 times more farnesol than do untreated cells. In our usage, subinhibitory means a concentration which causes a prominent decrease in turbidity but still allows some cell growth. METHODS: C. albicans A72 cells were grown overnight in 0-5.0 microM fluconazole, washed, and inoculated in mice by tail vein injection. Groups of 15 or 16 mice were injected with 1.3 x 10(6) cells and mortality was recorded for 7 days post-inoculation. The levels of farnesol in control and treated C. albicans were determined by GC/MS. RESULTS: The MIC50 for strain A72 was 0.125 mg/L (0.4 microM). Mice administered C. albicans pre-treated with 0.5 to 1.0 microM fluconazole died 2.5 to 4 days earlier and had 2 to 4 times higher mortality rates than mice given untreated C. albicans. Fluconazole (0.5 to 1.0 microM) pre-treated cells were 4.2 to 8.5 times more lethal (P < 0.001) than untreated cells. The extracellular, membrane bound, and intracellular farnesol concentrations of cells pre-treated with 1.0 muM fluconazole were 12-, 2- and 6-times those of untreated cells. CONCLUSIONS: The effects of fluconazole on C. albicans are very concentration-dependent. The enhanced pathogenicity of fluconazole pre-treated C. albicans in mice should be relevant to the therapeutic and prophylactic use of fluconazole. Further research is needed to explore whether farnesol production by C. albicans is a virulence factor.

Animals↗
PubMed1977

Hydrolysis and isomerization of trans,trans-farnesyl diphosphate by Andrographis tissue-culture enzymes.

Incubation of (3R,5S)-[5-3H1]mevalonate + (3RS)-[2-14C]mevalonate with Andrographis cell-free extract leads to trans,trans-farnesol and cis,trans-farnesol which both totally retain tritium. 2. This conflicts with our previous results which predict one third tritium loss in the cis,trans-farnesol. Inversion at C-1 during hydrolysis of trans,trans-farnesyl diphosphate to trans,trans-farnesol could explain this anomaly. 3. (1s)-trans,trans-[1-3H1]Farnesyl diphosphate and phosphate and (1R)-trans,trans-[1-3H1]-farnesyl diphosphate and phosphate, all prepared chemically, were hydrolysed with Andrographis phosphatase, and alkaline phosphatase and hydrogenolysed with lithium aluminium hydride and the product alcohols exchanged with liver alcohol hydrogenase. 4. Both Andrographis phosphatase and alkaline phosphatase hydrolyse trans,trans-farnesyl diphosphate and trans,trans-farnesyl phosphate with retention. 5. Hydrolysis of trans,trans-[1-18O]farnesyl diphosphate in H2(18O with both phosphatases supports P-O fission. 6. The C-1 configuration in (1S)-TRANS,TRANS-[1-3H1]farnesyl diphosphate and phosphate and (1R)-trans,trans-[1-3H1]farnesyl diphosphate and phosphate is progressively racemised in 0.01 M NH4OH/MeOH (1/9) AT - 20 degrees C.

Alkaline Phosphatase↗
PubMed2005

Release from quorum-sensing molecules triggers hyphal formation during Candida albicans resumption of growth.

Candida albicans is a pathogenic fungus able to change morphology in response to variations in its growth environment. Simple inoculation of stationary cells into fresh medium at 37 degrees C, without any other manipulations, appears to be a powerful but transient inducer of hyphal formation; this process also plays a significant role in classical serum induction of hyphal formation. The mechanism appears to involve the release of hyphal repression caused by quorum-sensing molecules in the growth medium of stationary-phase cells, and farnesol has a strong but incomplete role in this process. We used DNA microarray technology to study both the resumption of growth of Candida albicans cells and molecular regulation involving farnesol. Maintaining farnesol in the culture medium during the resumption of growth both delays and reduces the induction of hypha-related genes yet triggers expression of genes encoding drug efflux components. The persistence of farnesol also prevents the repression of histone genes during hyphal growth and affects the expression of putative or demonstrated morphogenesis-regulating cyclin genes, such as HGC1, CLN3, and PCL2. The results suggest a model explaining the triggering of hyphae in the host based on quorum-sensing molecules.

Candida albicans↗
PubMed1997

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors unmask cryptic regulatory mechanisms.

The possibility that potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may alter the mechanisms by which dietary cholesterol and farnesol regulate this gene was investigated by comparing the regulatory responses of rats maintained on diets with or without 0.04% Lovastatin supplementation to dietary cholesterol. It was found that the rate of hepatic HMG-CoA reductase transcription was significantly decreased by dietary cholesterol in animals fed Lovastatin-supplemented diets, whereas animals maintained on a normal chow diet showed no decrease in the rate of transcription. The levels of reductase mRNA were decreased to about 10% of controls in Lovastatin-supplemented animals in response to dietary cholesterol but not affected in nonsupplemented animals. Administration of farnesol, reputed to be the nonsterol regulator of reductase, to rats maintained on a diet containing Lovastatin decreased hepatic HMG-CoA reductase protein by 30% and the half-life of reductase immunoreactive protein to 4.0 h, which is close to that observed in chow-fed animals. In contrast, farnesol treatment does not affect the turnover rate of reductase protein in rats fed a normal chow diet. These results suggest that potent inhibitors of HMG-CoA reductase may unmask transcriptional regulation by dietary cholesterol and accelerated degradation of the reductase by the putative nonsterol regulator farnesol.

Animals↗
PubMed2002

Effects of compounds found in propolis on Streptococcus mutans growth and on glucosyltransferase activity.

Propolis, a resinous bee product, has been shown to inhibit the growth of oral microorganisms and the activity of bacterium-derived glucosyltransferases (GTFs). Several compounds, mainly polyphenolics, have been identified in this natural product. The present study evaluated the effects of distinct chemical groups found in propolis on the activity of GTF enzymes in solution and on the surface of saliva-coated hydroxyapatite (sHA) beads. Thirty compounds, including flavonoids, cinnamic acid derivatives, and terpenoids, were tested for the ability to inhibit GTFs B, C, and D from Streptococcus mutans and GTF from S. sanguinis (GTF Ss). Flavones and flavonols were potent inhibitors of GTF activity in solution; lesser effects were noted on insolubilized enzymes. Apigenin, a 4',5,7-trihydroxyflavone, was the most effective inhibitor of GTFs, both in solution (90.5 to 95% inhibition at a concentration of 135 microg/ml) and on the surface of sHA beads (30 to 60% at 135 microg/ml). Antibacterial activity was determined by using MICs, minimum bactericidal concentrations (MBCs), and time-kill studies. Flavanones and some dihydroflavonols, as well as the sesquiterpene tt-farnesol, inhibited the growth of S. mutans and S. sobrinus; tt-farnesol was the most effective antibacterial compound (MICs of 14 to 28 microg/ml and MBCs of 56 to 112 microg/ml). tt-Farnesol (56 to 112 microg/ml) produced a 3-log-fold reduction in the bacterial population after 4 h of incubation. Cinnamic acid derivatives had negligible biological activities. Several of the compounds identified in propolis inhibit GTF activities and bacterial growth. Apigenin is a novel and potent inhibitor of GTF activity, and tt-farnesol was found to be an effective antibacterial agent.

Animals↗
PubMed2006

The effect of terpene concentrations on the skin penetration of diclofenac sodium.

Terpenes and sesquiterpenes have been suggested as promising non-toxic, non-irritating transdermal penetration enhancers. This investigation aimed to study the effect of terpene concentration on the transdermal absorption of diclofenac sodium from ethanol:glycerin:phosphate buffer solution (60:10:30). Therefore, enhancing effects of various terpenes (menthone, limonenoxide, carvone, nerolidol and farnsol) with different concentrations (0.25, 0.5, 1, 1.5 and 2.5%, v/v) on the permeation of diclofenac sodium were evaluated using Franz diffusion cells fitted with rat skin. Furthermore, solubility of diclofenac sodium in the vehicle in presence of different concentrations of terpenes was determined. The results showed that despite the negligible effect of terpenes on the drug solubility, there was a profound skin penetration enhancement effect, although the terpene enhancers varied in their ability to enhance the flux of diclofenac sodium. The results showed that at the highest concentration of terpene (2.5%, v/v) the rank order of enhancement effect for diclofenac sodium was nerolidol>farnesol>carvone>methone>limonenoxide, whereas at the low concentration of 0.25% the rank order was farnesol>carvone>nerolidol>menthone>limonenoxide. No direct relationship existed between terpene concentration and the permeation rate. The most outstanding penetration enhancer was nerolidol, providing an almost 198-fold increase in permeability coefficient of diclofenac sodium, followed by farnesol with a 78-fold increase.

Administration, Cutaneous↗
PubMed2001

Impairment by lovastatin of neural relaxation of the rabbit sphincter of Oddi.

We sought whether inhibition of cholesterol biosynthesis by lovastatin influenced the nitrergic relaxation response of the sphincter of Oddi. Rabbit sphincters of Oddi rings were tested for changes in isometric tension in response to field stimulation in the presence of 4 microM guanethidine and 1 microM atropine. Tissue samples were then analyzed for cAMP and cGMP content by radioimmunoassay for nitric oxide concentration by electron spin resonance and for vasoactive intestinal peptide and calcitonin gene-related peptide (CGRP) release by radioimmunoassay. Membrane G(salpha) protein was determined by Western blot analysis. Field stimulation relaxed the preparations with an increase in nitric oxide, cAMP and cGMP concentrations at increased calcitonin gene-related peptide and vasoactive intestinal polypeptide (VIP) release. Preparations from rabbits pre-treated with lovastatin (5 mg/kg/day intragastrically, over 5 days) contracted under the same conditions with an attenuated cGMP-increase at preserved increase in NO content and neuropeptide release. The relaxation was recaptured combining lovastatin with farnesol (1 mg/kg intravenously, twice a day for 5 days). The field stimulation-induced increase in cyclic nucleotides was also restored. Lovastatin decreased membrane G(salpha) protein content, which was re-normalized by farnesol. Farnesol treatment reinstates neurogenic relaxation of the sphincter of Oddi deteriorated by lovastatin possibly by normalizing G-protein coupling.

Animals↗
PubMed1999

Inhibition of human B cell activation by a novel nonsteroidal anti-inflammatory drug, indometacin famesil.

Indometacin farnesil (INF) is a prodrug of indomethacin (IND) designed to reduce the occurrence of side-effects by esterification of the carboxyl group on IND with farnesol. Previous studies have shown that INF has the characteristics of disease-modifying anti-rheumatic drug (DMARD) in that it has a component of slow-acting effect in treatment of rheumatoid arthritis (RA), in which abnormal B cell functions are considered to be involved. The current studies therefore examined the effects of INF on human B cells. Ig production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. T cell proliferation and IFN-gamma production were induced from highly purified T cells by stimulation with immobilized mAb to CD3. At pharmacologically attainable concentrations, INF, but not IND, suppressed the production of IgM and IgG of B cells, whereas neither suppressed the T cell proliferation and IFN-gamma production. The inhibition of Ig production by INF is not due to its IND structure, but is most likely due to its farnesil component, since farnesol alone comparably suppressed the Ig production. INF and farnesol did not suppress the expression of early activation markers, including CD98, CD25, and CD71, on SA-stimulated B cells, but appeared to inhibit the maturation of B cells following the initial activation. These results indicate that INF preferentially suppresses the human B cell functions. Thus, the data suggest that INF may have more beneficial effects than IND in treatment of RA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1982

Enzymatic formation of nerolidol in cell-free extract of Rhodotorula glutinis.

Enzymatic formation of nerolidol was demonstrated by incubation of [14C]farnesyl pyrophosphate with the ultracentrifugal supernatant of cell-free extract of Rhodotorula glutinis. Farnesol was also formed concomitantly with the formation of nerolidol and the ratios of formation of both alcohols were from 1:3 to 1:4. Divalent cation was necessary for the reaction and Mn2+ was much more active than Mg2+ for nerolidol formation. No nerolidol was formed when farnesyl monophosphate or farnesol was used instead of farnesyl pyrophosphate as a substrate. Nerolidyl pyrophosphate or nerolidyl monophosphate could not be detected as an intermediate in the reaction. Based on these observations, nerolidol was presumed to be formed not via nerolidyl pyrophosphate or nerolidyl monophosphate but via a carbonium ion intermediate which was formed by cleavage of the carbon-oxygen bond of farnesyl pyrophosphate. This reaction seems to proceed in a similar manner to the acid hydrolysis of farnesyl pyrophosphate to form nerolidol and farnesol.

Farnesol↗
PubMed1996

Farnesyl analogues inhibit vasoconstriction in animal and human arteries.

Recent studies have suggested that nonsterol, mevalonate-derived metabolites are implicated in the control of vascular tone and blood pressure. Because of the metabolic importance of farnesyl pyrophosphate, a 15-carbon (C15) intermediate of the cholesterol pathway, the vasoactive properties of the farnesyl motif were investigated. Two farnesyl analogues were used: farnesol, the natural dephosphorylated form of farnesyl pyrophosphate, and N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins. Both compounds inhibited NE-induced vasoconstriction in rat aortic rings at micromolar concentration. Their action was rapid, dose dependent, and reversible. Shorter (C10) and longer (C20) isoprenols as well as N-acetyl-S-geranyl-L-cysteine (C10) did not inhibit the response to NE. In contrast, N-acetyl-S-geranylgeranyl-L-cysteine (C20), exhibited vasoactive properties similar to AFC. It was further demonstrated that AFC and farnesol inhibited KCl and NaF-induced contractions, suggesting a complex action on Ca2+ channels and G protein-dependent pathways. Finally, the effect of farnesol and AFC on the NE response was reproduced in human resistance arteries. In conclusion, mevalonate-derived farnesyl analogues are potent inhibitors of vasoconstriction. The study suggests that farnesyl cellular availability is an important determinant of vascular tone in animals and humans, and provides a basis for exploring farnesyl metabolism in humans with compromised vascular function as well as for using farnesyl analogues as regulators of arterial tone in vivo.

Animals↗
PubMed1984

Differentiation of mouse leukemic M1 cells induced by polyprenoids.

We screened several synthetic polyprenoids about their capacity of cell differentiation using mouse myeloid leukemic M1 cells, and found that 3, 7, 11, 15, 19,-pentamethyleicosa-2, 6, 10, 14, 18-pentaenol (Geranyl Farnesol) could induce the differentiation of M1 cells into macrophage-like cells. The optimal concentration of this compound for its induction capacity was approximately 2 X 10(-5) M. The induced differentiation related markers were morphological change in M1 cells, Fc receptors for IgG (Fc gamma), and non-specific esterase activity. However, phagocytic activity was poorly induced. This suggests that most of Geranyl Farnesol treated cells may be retained functionally incomplete macrophages. The presence of cycloheximide at 1 X 10(-7)M or the incubation of M1 cells at 4 degrees C completely blocked the induction of Fc gamma, suggesting the induction of Fc gamma required protein synthesis. The treatment of M1 cells with Geranyl Farnesol resulted in suppression of DNA and RNA synthesis. Further analysis of RNA metabolism suggested that the suppression of RNA synthesis was mainly due to the decrease of rRNA. On the other hand the synthesis and turnover of polyA-containing RNA (mRNA) rather increased.

Animals↗
PubMed1993

Characterization of mevalonate-labeled lipids isolated from parasite proteins in Schistosoma mansoni.

Adult paired schistosomes incubated for 3 days in radiolabeled mevalonate can effectively label at least 2 major proteins with apparent sizes of 25 and 43 kDa. The 25-kDa mevalonate-labeled proteins comigrated with proteins that could be labeled with GTP. The lipids attached to these proteins were removed and resolved by HPLC and found to comigrate with known samples of farnesol and geranylgeraniol. Homogenates of the schistosome when incubated with labeled farnesol pyrophosphate effectively labeled a protein(s) with an apparent molecular weight of 43 kDa while homogenates incubated in the presence of labeled geranylgeranyl pyrophosphate-labeled schistosome proteins with an apparent molecular weight of 25 kDa. Our results demonstrate that Schistosoma mansoni has the ability to covalently attach farnesol and geranylgeranyl to low-molecular weight proteins.

Animals↗
PubMed1999

Juvenile hormone biosynthesis in larval and adult stick insects, Carausius morosus.

Corpora allata (CA) from adult egg-carrying Indian stick insects, Carausius morosus, synthesise and release juvenile hormone (JH) III in vitro. No JH biosynthesis was observed in larvae, young adults, and old adult females that do not carry sclerotised eggs. In females, which bear sclerotised eggs, a consistent JH biosynthesis was observed. Supplementation of precursors of JH biosynthesis (farnesol, mevalonic acid lactone) greatly enhanced JH biosynthesis in a stage-, age-, and dose-dependent manner, but CA from the last larval instar retained the biosynthesised JH within the gland. Elevated calcium concentration in the incubation medium stimulated JH biosynthesis by CA from older adults but had either no or a poor effect on CA from young adults and larvae. The results obtained with farnesol, mevalonic acid lactone, and calcium indicate that the rate-limiting steps of JH biosynthesis very likely occur before the formation of mevalonic acid and that these early steps cannot be stimulated by elevated calcium concentrations in larvae and young adults. In older adults, in which spontaneous JH biosynthesis occurs, elevated calcium concentration can markedly stimulate JH biosynthesis. A pre-purified extract from brains of adult females had a stimulating effect on JH biosynthesis by CA from adult females. The results indicate that JH biosynthesis in C. morosus may require food-derived farnesol and may be regulated by allatotropic signals from the brain, possibly triggered by sclerotised oocytes in the ovary.

Journal Article↗
PubMed1978

Evidence from cell-free systems for differences in the sterol biosynthetic pathway of Rhizoctonia solani and Phytophthora cinnamomi.

Cell-free preparations of both Rhizoctonia solani, a sterol-synthesizing fungus, and Phytophthora cinnamomi, a non-sterol-synthesizing fungus, incubated in the presence of [2(-14)C]mevalonate and iodacetamide, converted the mevalonate into labelled mevalonate 5-phosphate, mevalonate 5-pyrophosphate and isopentenyl pyrophosphate. In the absence of iodoacetamide, but under anaerobic conditions, the same preparations converted the mevalonate into labelled geraniol, farnesol and squalene, the first two compounds presumably as their pyrophosphates. When cell-free preparations of both organisms were incubated aerobically in the presence of [1(-14)C]isopentenyl pyrophosphate, only labelled geraniol, farnesol and squalene were recovered from the P. cinnamomi reaction mixture, whereas labelled geraniol, farnesol, squalene, squalene epoxide, lanosterol and ergosterol were present in the R. solani reaction mixture. When these same preparations were incubated in the presence of 14C-labelled squalene, labelled squalene epoxide, lanosterol and ergosterol were recovered from the R. solani reaction mixture. In contrast, the P. cinnamomi preparation was unable to convert the squalene into products further along the sterol pathway; instead, a portion of the labelled squalene was converted into water-soluble products, indicating the possible existence of a squalene-degradation process in this organism. It appears that the block in the sterol biosynthetic pathway of P. cinnamomi occurs at the level of squalene epoxidation.

Alkenes↗
PubMed1980

Detection and partial characterization of activity of chlorophyll synthetase in etioplast membranes.

The esterification of chlorophyllide a was investigated an irradiated etioplast-membrane fractions ('broken etioplasts') from oat seedlings (Avena sativa L.). As a substrate, [1(-3)H]geranylgeraniol and its monophosphate and diphosphate derivatives were prepared by chemical synthesis. Geranylgeraniol and its monphosphate derivative are incorporated into chlorophyll only in the presence of ATP whereas the diphosphate derivative is incorporated also without ATP. The yield of esterified chlorophyll is 80-90% of chlorophyllide with saturating substrate concentrations. The term 'chlorophyll synthetase' is used to describe the enzyme activity which is different from chlorophyllase. Other substrates are phytol and farnesol either with ATP or as the diphosphate derivatives. The relative specificity of 'chlorophyll synthetase' for thse substrates is geranylgeraniol:phytol:farnesol = 6:3:1. In these experiments in vitro, a new chlorphyll esterified with farnesol was detected which does not occur in intact plants. Geraniol and n-pentadecanol are no substrates for the enzyme. Protochlorphyllide which is present in non-irradiated etioplast membrane fractions is not esterified under the same conditions.

Carbon-Oxygen Ligases↗
PubMed1997

Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier.

Members of the superfamily of nuclear hormone receptors which are obligate heterodimeric partners of the retinoid X receptor may be important in epidermal development. Here, we examined the effects of activators of the receptors for vitamin D3 and retinoids, and of the peroxisome proliferator activated receptors (PPARs) and the farnesoid X-activated receptor (FXR), on the development of the fetal epidermal barrier in vitro. Skin explants from gestational day 17 rats (term is 22 d) are unstratified and lack a stratum corneum (SC). After incubation in hormone-free media for 3-4 d, a multilayered SC replete with mature lamellar membranes in the interstices and a functionally competent barrier appear. 9-cis or all-trans retinoic acid, 1,25 dihydroxyvitamin D3, or the PPARgamma ligands prostaglandin J2 or troglitazone did not affect the development of barrier function or epidermal morphology. In contrast, activators of the PPARalpha, oleic acid, linoleic acid, and clofibrate, accelerated epidermal development, resulting in mature lamellar membranes, a multilayered SC, and a competent barrier after 2 d of incubation. The FXR activators, all-trans farnesol and juvenile hormone III, also accelerated epidermal barrier development. Activities of beta-glucocerebrosidase and steroid sulfatase, enzymes previously linked to barrier maturation, also increased after treatment with PPARalpha and FXR activators. In contrast, isoprenoids, such as nerolidol, cis-farnesol, or geranylgeraniol, or metabolites in the cholesterol pathway, such as mevalonate, squalene, or 25-hydroxycholesterol, did not alter barrier development. Finally, additive effects were observed in explants incubated with clofibrate and farnesol together in suboptimal concentrations which alone did not affect barrier development. These data indicate a putative physiologic role for PPARalpha and FXR in epidermal barrier development.

Animals↗
PubMed2002

Alendronate inhibits invasion of PC-3 prostate cancer cells by affecting the mevalonate pathway.

Breast and prostate cancer preferentially metastasize in the skeleton, inducing locally increased bone resorption by osteoclasts. Bisphosphonates (BPs), potent inhibitors of osteoclasts and bone resorption, are able to reduce metastatic bone lesions, but the metastasis-related cellular target molecules for BPs have not yet been identified. In osteoclasts, nitrogen-containing BPs inhibit the function of the mevalonate pathway, impairing the prenylation and activation of small GTPases. In addition, direct effects of BPs on cancer cells have been suggested. In the present study, the effects of two clinically used BPs, the amino-BP alendronate and clodronate, on adhesion, invasion, and migration of human PC-3 prostate cancer cells were examined in vitro. We also studied the possible role of the mevalonate pathway in invasion and migration of PC-3 cells using the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitor mevastatin and the mevalonate pathway intermediates mevalonate (mevalonic acid lactone), geranylgeraniol, and trans-trans-farnesol. The results demonstrate that alendronate pretreatment very effectively inhibited in vitro invasion of prostate cancer cells in a dose-dependent manner, with an IC50 as low as approximately 1 pM. The inhibition was similar to that of mevastatin. Clodronate also inhibited invasion, but the IC50 was 0.1 microM. Importantly, geranylgeraniol and trans-trans-farnesol reversed the inhibitory effect of alendronate and mevastatin but not the clodronate-induced inhibition of invasion. Alendronate pretreatment also inhibited migration, which was partially reversed by geranylgeraniol and trans-trans-farnesol. Adhesion of PC-3 cells to various matrices was reduced, and their F-actin organization was changed. Alendronate pretreatment also inhibited invasion of human Du-145 prostate and MDA-MB-231 breast cancer cells. As a conclusion, the results demonstrate that the mevalonate pathway leading to protein prenylation is important for cancer cell invasion and migration in vitro. They further suggest that interference with this pathway is involved in inhibition of invasion and migration of prostate cancer cells by the amino-BP alendronate but that the mechanism of clodronate inhibition is different. It is possible that BPs have therapeutic potential in preventing the spread of prostate cancer.

Alendronate↗
PubMed1999

In vivo prenylation of rat proteins: modification of proteins with penta- and hexaprenyl groups.

In vivo protein prenylation was studied in newborn rats by repeated injections of [3H]mevalonate. The highest level of protein-bound mevalonate metabolites was found in the kidney, but incorporation was observed in all organs studied. After fluorography of SDS-polyacrylamide gel electrophoresis-separated polypeptides, labeling was found in the 21- to 28-kDa molecular mass region and, after prolonged exposure of the film, additional bands at both higher and lower molecular masses could be detected. Protein prenylation in the kidney increased during the first 5 days after birth, whereas that in the liver reached a maximum on the fourth day. After methyliodide treatment of the prenylated proteins, farnesol, geranylgeraniol, and two larger isoprenoids, pentaprenol and hexaprenol, were released. In the liver, the ratio of protein-bound geranylgeraniol to farnesol increased from 2 to 4.5 during the first 5 days after birth. Upon subfractionation of the kidney, the highest level of labeling was found in mitochondria and microsomes. When the mitochondria were subfractionated into outer membranes, intermembrane space and an inner membrane/matrix fraction, the labeling pattern of prenylated polypeptides differed in all fractions. The results demonstrate that in vivo labeling of rats can be performed to study the extent, type, and distribution of protein prenylation.

Animals↗