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At least 19 recordsLinked to original sources
PubMed1995

Mechanism of farnesol cytotoxicity: further evidence for the role of PKC-dependent signal transduction in farnesol-induced apoptotic cell death.

Mechanism of the inhibitory effect of isoprenoid farnesol on cell proliferation has been studied in human acute leukemia CEM-C1 cells. Farnesol (20 microM) reduced the rate of radioactive label incorporation into cellular diacylglycerol (DAG) and phosphocholine, the products of degradation of phosphatidylcholine (PC), indicating inhibition of PC-specific phospholipase C after about 1 h of incubation. Inhibition of phospholipase D by farnesol at the later incubation time (about 2 h) was demonstrated by a decrease in synthesis of PC-derived phosphatidylethanol in the presence of ethanol. These effects of farnesol on PC degradation and formation of DAG were followed by apoptotic fragmentation of cellular DNA and inhibition of cell growth. Exogenous DAG reduced the level of DNA fragmentation and cell growth inhibition. Results are consistent with the involvement of cellular signal transduction in the mechanism of inhibition of cell proliferation by farnesol.

Acute Disease↗
PubMed1974

Biosynthesis of trans, trans- and cis, trans-farnesols by soluble enzymes from tissue cultures of Andrographis paniculata.

A cell-free system obtained from tissue cultures of Andrographis paniculata produces 2-trans,6-trans-farnesol (trans,trans-farnesol) and 2-cis,6-trans-farnesol (cis,trans-farnesol) (5:1), incorporating 10% of the radioactivity from 3R-[2-(14)C]mevalonate. There is total loss of (3)H from 3RS-[2-(14)C,(4S)-4-(3)H(1)]mevalonate and total retention from the (4R) isomer in both the trans,trans-farnesol and cis,trans-farnesol formed. When 3RS-[2-(14)C,5-(3)H(2)]mevalonate is used as substrate, there is total retention of (3)H in the trans,trans-farnesol, but loss of one-sixth of the (3)H in the cis,trans-farnesol. With (1R)- and (1S)-[4,8,12-(14)C(3),1-(3)H(1)]-trans,trans -farnesol and (1R)- and (1S)-[4,8,12-(14)C(3),1-(3)H(1)]-cis, trans-farnesol as substrates, the label is lost from the (1R)-cis,trans and (1S)-trans,trans isomers but retained in the (1R)-trans,trans and (1S)-cis,trans isomers; this shows that the pro-1S hydrogen is exchanged in the conversion of trans,trans-farnesol into cis,trans-farnesol and the pro-1R hydrogen in the conversion of cis,trans-farnesol into trans,trans-farnesol. (1R)-[1-(3)H(1)]-trans,trans-Farnesol and (1R)-[1-(3)H(1)]-cis,trans-farnesol have been synthesized by asymmetric chemical synthesis and exchanged with liver alcohol dehydrogenase. Both the trans- and the cis-alcohol exchange the pro-1R hydrogen atom.

Chemical Phenomena↗
PubMed1993

Farnesol inhibits phosphatidylcholine biosynthesis in cultured cells by decreasing cholinephosphotransferase activity.

The mechanism of inhibition of phosphatidylcholine (PC) biosynthesis by the isoprenoid farnesol was investigated in the human leukaemic CEM-C1 cell line. Cells were preincubated with 20 microM farnesol for up to 2 h and pulsed with [3H]choline. PC biosynthesis was inhibited to one-quarter at the step catalysed by cholinephosphotransferase (CPT). CPT activity in cellular homogenates from farnesol-treated cells was significantly decreased, but no changes in cytidylyltransferase activity or diacylglycerol concentration were observed. Measurements of CPT activity in the experiments in which farnesol was added directly to the homogenates or microsomal fractions demonstrated that farnesol did not affect CPT activity. However, cytosol from farnesol-treated samples decreased microsomal CPT activity almost twice as much as did cytosol from controls. This effect was found to be heat-stable, and disappeared after dialysis, but could not be attributed to farnesol present in the cytosol. The effect of farnesol was specific when compared with other structurally similar isoprenoids. We conclude that farnesol brings about changes in cultured cells, leading to decreased CPT activity, and thus to the inhibition of PC biosynthesis.

Choline↗
PubMed1983

Farnesol and farnesal dehydrogenase(s) in corpora allata of the tobacco hornworm moth, Manduca sexta.

The metabolism of [3H]farnesol was studied in cell-free preparations of corpora allata from the tobacco hornworm, Manduca sexta, to assess the role of this presumed biosynthetic precursor of juvenile hormone (JH) III. A reversed-phase ion-pair liquid chromatographic (RP-IPC) procedure was devised to separate farnesol from several potential intermediates in its presumed metabolism to JH III: farnesal, farnesoic acid, 10,11-epoxyfarnesoic acid, and methyl farnesoate. Following incubation of (2E,6E)-[1,5,9-3H]farnesol with homogenates of corpora allata from fifth instar larvae or adult female M. sexta, and analysis by RP-IPC, the major radiolabeled products corresponded to farnesoic acid, farnesal, and a polar product(s) presumably derived from the tritium on C-1 of farnesol. Inclusion of NAD+ in the incubations conducted with crude homogenates resulted in enhanced [3H]farnesol metabolism, decreased accumulation of [3H]farnesal, and increased levels of [3H]farnesoic acid. Substitution of NADP+ for NAD+ was ineffective, suggesting that farnesol and/or farnesal dehydrogenase were NAD+-dependent enzymes. Pellet fractions obtained by differential centrifugation of crude homogenates exhibited both farnesol and farnesal dehydrogenase activity but only the latter was clearly stimulated by addition of NAD+. The alcohol/aldehyde dehydrogenase(s) showed some substrate specificity for the 2E isomer; nerol and (2Z,6E)-farnesol were barely metabolized under conditions in which either geraniol or (2E,6E)-farnesol were rapidly oxidized. The identity of the [3H]farnesal zone obtained from RP-IPC was further established by normal-phase liquid chromatography and by gas-liquid chromatography-mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Oxidoreductases↗
PubMed1991

Effects of farnesol and the off-flavor derivative geosmin on Streptomyces tendae.

Effects of the sesquiterpene farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) and the sesquiterpene derivative geosmin (1,10-trans-dimethyl-trans-9-decalol) were investigated in a geosmin-producing actinomycete, Streptomyces tendae. Exposure to 300 microM farnesol reduced biomass (fresh matter) accumulation by 97% compared with biomass accumulation by controls, whereas an equal amount of geosmin did not affect biomass accumulation. Increasing exposure to farnesol corresponded with reduced optical density of the culture, reduced levels of geosmin, and reduced metabolic heat production compared with controls, while exogenous geosmin did not affect these parameters. Geosmin dissipated from unioculated medium more rapidly than farnesol, indicating that in addition to the lower toxicity of geosmin, the actual exposure to geosmin over time may be less than exposure to an equal amount of farnesol. Cultures grown on Actinomyces-B medium contained 99.5% less geosmin and were more sensitive to farnesol than those grown on Hickey-Tresner medium, indicating that geosmin synthesis was associated with reduced sensitivity to farnesol. Consumption of farnesyl moieties during geosmin synthesis may reduce the potential for farnesol-induced inhibition of growth and metabolism.

Farnesol↗
PubMed1995

Selective farnesol toxicity and translocation of protein kinase C in neoplastic HeLa-S3K and non-neoplastic CF-3 cells.

We have reported earlier that farnesol, a 15 carbon isoprenoid, has inhibitory effects on the growth and viability of a variety of cultured cells of neoplastic derivation but is considerably less cytotoxic to cells derived from normal tissue (Cancer Lett., 79, 175-179). As part of our search for the mechanism of this observation, we have studied the effect of 20 microM farnesol on the distribution of protein kinase C (PKC) between cytosolic and membrane fractions of HeLa S3K cells and fibroblasts line CF-3. In HeLa cells farnesol caused translocation of PKC from membrane fraction to cytosol after 1h of incubation and also prevented PMA-stimulated induction of PKC translocation from cytosol to membranes. Up to 6 h of incubation, there was no effect of farnesol on PKC localization in CF-3 fibroblasts. The results point to possible involvement of PKC in the toxic effect of farnesol which occurs with some degree of selectivity depending on cell origin.

Cell Membrane↗
PubMed1994

Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

The degradation of the microsomal enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is highly regulated and is dependent on both a sterol and non-sterol derivative of mevalonic acid (MVA). We recently proposed that the non-sterol component is derived from farnesyl diphosphate (FPP), presqualene pyrophosphate, or squalene (Correll, C. C. and Edwards, P. A. (1994) J. Biol. Chem. 269, 633-638). In the current study, we have used digitonin-permeabilized cells to further define this MVA-derived non-sterol component required for the regulated degradation of HMG-CoA reductase. The addition of either FPP or farnesol to digitonin-permeabilized cells resulted in a rapid and dose-dependent degradation of HMG-CoA reductase. The effect of FPP, but not farnesol, was blocked by the phosphatase inhibitor sodium fluoride. The enhanced degradation of HMG-CoA reductase in permeabilized cells specifically required farnesol, since the addition of any of the structurally related isoprenoids geraniol, geranyl diphosphate, geranylgeranyl diphosphate, nerolidol, or all-cis-farnesol, or of the non-sterol squalene to the permeabilized cells did not stimulate enzyme degradation. The present studies demonstrate for the first time that the accelerated degradation of HMG-CoA reductase can be initiated in vitro. Further, since farnesol is shown to be specifically required for the enhanced degradation of the enzyme in vitro, we propose that this isoprenoid alcohol is important in this process in intact cells.

Animals↗
PubMed1994

Effects of farnesol on the thermotropic behavior of dimyristoylphosphatidylcholine.

Differential scanning calorimetry (DSC) and DPH fluorescence anisotropy have been used to investigate the effects of trans-trans farnesol on the physical properties of model membranes and extracted cell lipids. Farnesol was shown to have a significant effect on the gel to liquid-crystal phase transition temperature, the enthalpy of the transition and the transition co-operativity for extruded vesicles of dimyristoylphosphatidylcholine (DMPC). The phase transition of DMPC vesicles was eliminated at 25 mol% farnesol. Farnesol decreased the fluorescence anisotropy of the lipids extracted from human leukemia line CEM-C1 cells.

Dimyristoylphosphatidylcholine↗
PubMed1994

Directed cell killing (apoptosis) in human lymphoblastoid cells incubated in the presence of farnesol: effect of phosphatidylcholine.

Previously reported observations have shown that trans-trans farnesol inhibits incorporation of choline into phosphatidylcholine and reduces the growth rate of the human acute leukemia CEM-C1 cell line (Melnykovych, G., Haug, J.S. and Goldner, C.M. (1992) Biochem. Biophys. Res. Commun. 186, 543-548). These findings have now been followed up in order to establish a relationship between the inhibition of phosphatidylcholine synthesis and the ensuing cell shrinkage and cell death which takes place at higher concentrations of farnesol or upon long incubation. The present results show that after incubation in the presence of farnesol the cells decrease in viability. Their nuclear DNA becomes fragmented at internucleosomal linker regions, showing characteristic pattern of bands at 180 to 200 base-pair intervals. This farnesol-induced effect was also demonstrated by flow cytometry by staining the cellular DNA with propidium iodide and was partially reversible with phosphatidylcholine.

Apoptosis↗
PubMed1995

Metabolism of [3H]farnesol to cholesterol and cholesterogenic intermediates in the living rat eye.

Adult rats were injected intravitreally with all-trans [1-3H]farnesol, with or without co-injection of the squalene epoxidase inhibitor NB-598. Retinas were isolated 16 h later and their lipids were extracted, saponified, and analyzed by radio-HPLC. Most (> or = 90%) of the nonsaponifiable radioactivity was recovered as unmetabolized [3H]farnesol; however, about 6-8% of the radioactivity in control retinas exhibited the chromatographic behavior of sterols, including cholesterol. Unlike the controls, the NB-598-treated retinas exhibited substantial accumulation of both [3H]squalene and squalene mass. Calculations indicate that most of the squalene mass was derived from metabolism of endogenous precursors, with an in vivo biosynthetic rate of 46 +/- 17.5 pmol/retina/h. Retinas from eyes injected with all-trans [1-3H]geranylgeraniol yielded only the unmetabolized precursor in the nonsaponifiable extracts. These results suggest that farnesol can be "activated" in vivo (presumably to the corresponding allylic pyrophosphate) in the retina and subsequently metabolized to sterols and sterol precursors.

Animals↗
PubMed1972

Dolichols, ubiquinones, geranylgeraniol and farnesol as the major metabolites of mevalonate in Phytophthora cactorum.

Farnesol, geranylgeraniol, dolichols and ubiquinones were the main radioactive components of the unsaponifiable lipid recovered from Phytophthora cactorum grown in aerated cultures containing [2-(14)C]mevalonate. The (14)C recovered in each of these components was in the approximate proportion 2:4:3:5. When the culture was not aerated no radioactive ubiquinone was recovered. Most of the (14)C recovered in the dolichols was found in dolichol-15 (37%), with decreasing amounts in dolichol-14 (30%) and -13 (14%) and only a little (5%) in dolichol-16, whereas the major components, by weight, of the mixture (13mug/g of damp-dry tissue) were dolichol-14, -15 and -16 in the approximate proportion of 1:3:1. Radioautography of appropriate chromatograms indicated the presence also of traces of radioactivity in dolichol-9, -10, -11, -12 and -17. Most (80%) of the (14)C recovered in the ubiquinones was associated with ubiquinone-9, the rest being in ubiquinone-8. Most (80%) of the weight of ubiquinones (19mug/g of damp-dry tissue) was also ubiquinone-9. The identification of these compounds was by chromatographic methods and, for the ubiquinones and dolichols, was confirmed by mass spectrometry. In addition, the incorporation of 4R- and/or 4S-(3)H from [4-(3)H]-mevalonates showed the expected stereochemistry of biosynthesis, namely that farnesol, geranylgeraniol and ubiquinones were biogenetically all trans and the dolichols each contained three biogenetically trans isoprene residues, the remaining residues being biogenetically cis. The distribution of (14)C in the components of the whole lipid of the fungus was consistent with 97% of both the farnesol and geranylgeraniol being present as the fatty acid ester. The corresponding value for dolichols was 37%. The observation by other workers, that this fungus does not form either squalene or sterol, was confirmed.

Alcohols↗
PubMed1976

The in vitro effects of farnesol and derivatives on Hymenolepis diminuta.

Employing an in vitro maintenance system, in which 8-day-old Hymenolepis diminuta survives for 24 hr (Fioravanti and MacInnis, 1976), it was found that farnesol or farnesal supplementation of the medium had no beneficial effects on maintenance and these substances induced necrosis at higher concentrations. Similar experiments utilizing Schiller's (1965) culture system demonstrated that neither farnesol, farnesal, nor farnesyl methyl ether exhibited growth promoting effects and were toxic to the worms at higher concentrations. In addition, neither the 2-cis, 6-trans nor the 2-trans, 6-trans-isomers of farnesol promoted growth in the Schiller system and at higher concentrations resulted in severe necrosis within 24 hr.

Animals↗
PubMed1994

Phosphorylation of farnesol by a cell-free system from Botryococcus braunii.

Farnesol was incorporated into squalene as well as botryococcenes when the alcohol was fed to the culture of Botryococcus braunii B race strain. In in vitro experiments with a 10,000 x g supernatant of cell homogenate, squalene was synthesized from farnesyl diphosphate in the presence of NADPH or NADH, but botryococcenes were not synthesized under the same conditions. A 100,000 x g pelet fraction was able to phosphorylate farnesol to give its mono- and diphosphate esters in a CTP dependent manner.

Cytidine Triphosphate↗
PubMed1995

Identification of a nuclear receptor that is activated by farnesol metabolites.

Nuclear hormone receptors comprise a superfamily of ligand-modulated transcription factors that mediate the transcriptional activities of steroids, retinoids, and thyroid hormones. A growing number of related proteins have been identified that possess the structural features of hormone receptors, but that lack known ligands. Known as orphan receptors, these proteins represent targets for novel signaling molecules. We have isolated a mammalian orphan receptor that forms a heterodimeric complex with the retinoid X receptor. A screen of candidate ligands identified farnesol and related metabolites as effective activators of this complex. Farnesol metabolites are generated intracellularly and are required for the synthesis of cholesterol, bile acids, steroids, retinoids, and farnesylated proteins. Intermediary metabolites have been recognized as transcriptional regulators in bacteria and yeast. Our results now suggest that metabolite-controlled intracellular signaling systems are utilized by higher organisms.

Amino Acid Sequence↗
PubMed1992

Growth inhibition of leukemia cell line CEM-C1 by farnesol: effects of phosphatidylcholine and diacylglycerol.

Acute leukemia cells of the established line CEM-C1 were treated during growth in serum-free medium with various concentrations of trans-trans farnesol. At concentrations ranging from 9.0 to 31.5 microM, farnesol inhibited growth of these cells without causing cell lysis. This effect was preceded by very rapid inhibition of choline incorporation in cellular lipid fraction. The growth inhibitory effect was prevented to a large extent by incubation with phosphatidylcholine or diacylglycerol.

Acyclic Monoterpenes↗
PubMed1990

Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation.

Oncogenic forms of ras proteins are synthesized in the cytosol and must become membrane associated to cause malignant transformation. Palmitic acid and an isoprenoid (farnesol) intermediate in cholesterol biosynthesis are attached to separate cysteine residues near the C termini of H-ras, N-ras, and Kirsten-ras (K-ras) exon 4A-encoded proteins. These lipid modifications have been suggested to promote or stabilize the association of ras proteins with membranes. Because preventing isoprenylation also prevents palmitoylation, examining the importance of isoprenylation alone has not been possible. However, the oncogenic human [Val12]K-ras 4B protein is not palmitoylated but is isoprenylated, membrane associated, and fully transforming. We therefore constructed mutant [Val12]K-ras 4B proteins that were not isoprenylated to examine the effects of isoprenylation in the absence of palmitoylation. The nonisoprenylated mutant proteins both failed to associate with membranes and did not transform NIH 3T3 cells. In addition, inhibition of isoprenoid and cholesterol synthesis with the drug compactin also decreased [Val12]K-ras 4B protein isoprenylation and membrane association. These results unequivocally demonstrate that isoprenylation, rather than palmitoylation, is essential for ras membrane binding and ras transforming activity. These findings clearly indicate the biological significance of ras protein modification by farnesol and suggest that this modification may be important for facilitating the processing, trafficking, and biological activity of other isoprenylated proteins. Because K-ras is the most frequently activated oncogene in a wide spectrum of human malignancies, study of this pathway could lead to important therapeutic treatments.

Animals↗