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PubMed2001

Farnesol oxidation in insects: evidence that the biosynthesis of insect juvenile hormone is mediated by a specific alcohol oxidase.

The oxidation of farnesol to farnesoic acid is a key step in insect juvenile hormone biosynthesis. We herein present preliminary characterization of the enzyme-catalyzed oxidation of farnesol to farnesal in larval corpora allata homogenates of the tobacco hornworm, Manduca sexta. This conversion, which is highly substrate specific, has a K(m) apparent of 1 microM and a pH optimum between 6 and 7. Results from chemical modification experiments indicate that the enzyme possesses an active site tyrosine residue. Although farnesol oxidation in adult M. sexta corpora allata homogenates was previously identified as being catalyzed by a dehydrogenase, the corresponding conversion in larvae is not effected by the addition of nicotinamide cofactors. Instead, enzymatic activity is slightly enhanced by the addition of FAD, decreases when incubations are performed anaerobically, and is completely inhibited when either sodium dithionite or glucose oxidase is added. Although the effect of various additives suggests that the oxidation of farnesol to farnesal does not require a metal redox center, 1,10-phenanthroline (but not 4,7-phenanthroline) is a weak irreversible inhibitor of farnesol oxidation (IC(50)=11 mM). The addition of exogenous metals (Fe2+, Cu2+, Ni2+, and Co2+) caused differential effects on farnesol metabolism, with Cu2+ being highly inhibitory. Taken together, this data suggests that the oxidation of farnesol to farnesal in larval corpora allata is mediated by a specific oxygen-dependent enzyme, perhaps a flavin and/or iron-dependent oxidase.

Alcohol Oxidoreductases↗
PubMed2003

Inhibition of Streptococcus mutans biofilm accumulation and polysaccharide production by apigenin and tt-farnesol.

OBJECTIVES: Apigenin is a potent inhibitor of glucosyltransferases and tt-farnesol affects the membrane integrity of Streptococcus mutans. We investigated the influence of apigenin and tt-farnesol, alone and in combination, on the accumulation, polysaccharide composition and viability of S. mutans UA159 biofilms. METHODS: Initially, biofilms were grown for 54 h; then, the early-formed biofilms were treated for 1 min twice daily with one of the following: (i). 1.33 mM tt-farnesol; (ii). 1.33 mM apigenin; (iii). apigenin + tt-farnesol (1.33 mM each); (iv). vehicle control (20% ethanol with 0.75% dimethyl sulphoxide); (v). 0.12% chlorhexidine (1.33 mM); or (vi). physiological saline (145 mM NaCl). The procedure was repeated at biofilm ages of 78 and 102 h, and biofilms were harvested at 126 h. The dry weight, protein concentration, number of cfu, and polysaccharide composition per biofilm were determined. RESULTS: The dry weights of the biofilms treated with the test agents were significantly less (30-50%) than those treated with vehicle control (P < 0.05). Biofilms treated with the test agents also resulted in lower amounts of extracellular alkali-soluble glucans, intracellular iodophilic polysaccharides and, to a lesser extent, fructans. The fructosyltransferase activity was affected only by apigenin and apigenin + tt-farnesol. The recoverable viable counts of S. mutans were slightly lower (0.5 to 1 log10 decrease in cfu/biofilm) after apigenin and tt-farnesol treatments compared with the vehicle control. Chlorhexidine displayed potent bactericidal activity, and virtually halted the further accumulation of early-formed (54 h old) biofilms. CONCLUSIONS: Apigenin and tt-farnesol affected the accumulation and polysaccharide content of S. mutans biofilms without major impact on the bacterial viability.

Anti-Infective Agents, Local↗
PubMed2005

Enhanced apoptosis through farnesol inhibition of phospholipase D signal transduction.

Farnesol is a catabolite of the cholesterol biosynthetic pathway that preferentially causes apoptosis in tumorigenic cells. Phosphatidylcholine (PC), phosphatidic acid (PA), and diacylglycerol (DAG) were able to prevent induction of apoptosis by farnesol. Primary alcohol inhibition of PC catabolism by phospholipase D augmented farnesol-induced apoptosis. Exogenous PC was unable to prevent the increase in farnesol-induced apoptosis by primary alcohols, whereas DAG was protective. Farnesol-mediated apoptosis was prevented by transformation with a plasmid coding for the PA phosphatase LPP3, but not by an inactive LPP3 point mutant. Farnesol did not directly inhibit LPP3 PA phosphatase enzyme activity in an in vitro mixed micelle assay. We propose that farnesol inhibits the action of a DAG pool generated by phospholipase D signal transduction that normally activates an antiapoptotic/pro-proliferative target.

Animals↗
PubMed2002

Inhibition of Candida albicans biofilm formation by farnesol, a quorum-sensing molecule.

Farnesol is a quorum-sensing molecule that inhibits filamentation in Candida albicans. Both filamentation and quorum sensing are deemed to be important factors in C. albicans biofilm development. Here we examined the effect of farnesol on C. albicans biofilm formation. C. albicans adherent cell populations (after 0, 1, 2, and 4 h of adherence) and preformed biofilms (24 h) were treated with various concentrations of farnesol (0, 3, 30, and 300 micro M) and incubated at 37 degrees C for 24 h. The extent and characteristics of biofilm formation were then assessed microscopically and with a semiquantitative colorimetric technique based on the use of 2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide. The results indicated that the effect of farnesol was dependent on the concentration of this compound and the initial adherence time, and preincubation with 300 micro M farnesol completely inhibited biofilm formation. Supernatant media recovered from mature biofilms inhibited the ability of planktonic C. albicans to form filaments, indicating that a morphogenetic autoregulatory compound is produced in situ in biofilms. Northern blot analysis of RNA extracted from cells in biofilms indicated that the levels of expression of HWP1, encoding a hypha-specific wall protein, were decreased in farnesol-treated biofilms compared to the levels in controls. Our results indicate that farnesol acts as a naturally occurring quorum-sensing molecule which inhibits biofilm formation, and we discuss its potential for further development and use as a novel therapeutic agent.

Animals↗
PubMed2005

Alleviation of free radical mediated oxidative and genotoxic effects of cadmium by farnesol in Swiss albino mice.

Farnesol is an isoprenoid found in essential oils of ambrette seeds, citronella and in various aromatic plants. Exposure to cadmium from various sources affects the renal system adversely and Cd is an established genotoxic agent. In the present study, we evaluated the antigenotoxic and antioxidant efficacy of farnesol against cadmium chloride (CdCl2)-induced renal oxidative stress and genotoxicity in Swiss albino mice. Single, intraperitoneal doses of CdCl2(5 mg/kg body weight) for 24 h resulted in a significant (P < 0.001) increase in chromosomal aberration and micronuclei formation. The oral administration of farnesol at two doses (1% and 2% per kg body weight) for seven consecutive days showed significant (P < 0.05) suppression of the genotoxic effects of CdCl2 in the modulator groups. To study the mechanism by which farnesol exerts its antigenotoxic potential, enzymes involved in metabolism and detoxification were estimated. CdCl2 intoxication adversely affected the renal antioxidant armory and increased TBARS formation and xanthine oxidase levels significantly (P < 0.001). Farnesol showed a significant (P < 0.001) recovery in antioxidant status viz, GSH content (and its dependent enzymes) and catalase activity. Farnesol pretreatment in CdCl2-intoxicated mice showed marked (P < 0.001) suppression of TBARS' formation and XO activity. Our results support the conclusion that the anticlastogenic effect of farnesol could be due to restoration of antioxidants and inhibition of oxidative damage.

Animals↗
PubMedDate not supplied

Effects of the isoprenoids perillyl alcohol and farnesol on apoptosis biomarkers in pancreatic cancer chemoprevention.

Perillyl alcohol, farnesol and geraniol have chemotherapeutic activity toward pancreatic and other cancers. Perillyl alcohol induces apoptosis and increases expression of the proapoptotic protein Bak in cultured pancreatic tumor cells. We tested the hypothesis that farnesol and geraniol would have similar effects. After 48 hours of treatment with farnesol geraniol or perillyl alcohol, human BxPC3 pancreatic cancer cells exhibited a 3 to 10-fold increase in apoptosis and higher Bak expression than the controls. We then tested the hypotheses that perillyl alcohol and farnesol would have chemopreventive activity toward pancreatic cancer and would increase Bak expression and apoptosis in vivo. Hamster pancreatic cancer was initiated at time 0 with N-nitrosobis(2-oxopropyl)amine. Animals were fed control, 2% (w/w) perillyl alcohol, or 1% (w/w) farnesol diets from weeks 5-42. Pancreatic carcinoma incidence was decreased by perillyl alcohol and farnesol. Hyperplastic pancreatic ductal neoplasms from perillyl alcohol and farnesol-treated animals had higher Bak protein expression (p < 0.05), and somewhat higher apoptotic rates, diminished expression of the antiapoptotic protein BCL-XL, and lower rates of DNA synthesis than the controls.

Animals↗
PubMed2006

Farnesol induces thyroid hormone receptor (THR) beta1 but inhibits THR-mediated signaling in MCF-7 human breast cancer cells.

Anti-cancer effects of farnesol are well established, although mechanisms mediating these effects are not fully understood. Since farnesol has been shown to regulate gene transcription through activation of the farnesoid X receptor and the peroxisome proliferator-activated receptors-alpha and -gamma, we hypothesized that farnesol may also mediate some of its effects through other nuclear hormone receptors. Here we showed that in MCF-7 human breast cancer cells, farnesol induced the expression of thyroid hormone receptor (THR) beta1 mRNA and protein at concentrations that inhibited cell growth. Changes in the expression of THR responsive genes, however, suggested that farnesol inhibits THR-mediated signaling. Protein extracts from cells treated with farnesol displayed decreased binding to oligodeoxynucleotides containing a consensus sequence for the THR response element, despite the higher THRbeta1 content, providing a mechanism to explain the decreased transcriptional activity of cellular THRs.

Breast Neoplasms↗
PubMed2002

Farnesol as an inhibitor and substrate for rabbit liver microsomal P450 enzymes.

Farnesol and the related isoprenoids, geranylgeraniol, geranylgeranyl pyrophosphate, and farnesyl pyrophosphate, are produced in the endoplasmic reticulum of hepatocytes in mammals, and each serve important biological functions. Of these compounds, only farnesol was shown to significantly inhibit rabbit liver microsomal cytochrome P450 enzymes. The observed inhibition appeared to be reversible, and was not strictly competitive, but rather mixed in nature. Of the activities examined, ethoxycoumarin de-ethylase and diclofenac-4-hydroxylase activities were most sensitive to farnesol, with K(I) and K(I)' values between 11 and 40 microM. Caffeine-8-hydroxylation and taxol-6-hydroxylation were not inhibited at all by farnesol. Farnesol appeared to be a P450 substrate, as well as an inhibitor, as indicated by the NADPH-dependent decrease in farnesol concentration in microsomal incubations, and the metabolism was inhibited by CO, which pointed to the involvement of P450 isozymes.

Animals↗
PubMed1999

Modulation of neuronal voltage-gated calcium channels by farnesol.

The modulation of presynaptic voltage-dependent calcium channels by classical second messenger molecules such as protein kinase C and G protein betagamma subunits is well established and considered a key factor for the regulation of neurotransmitter release. However, little is known of other endogenous mechanisms that control the activity of these channels. Here, we demonstrate a unique modulation of N-type calcium channels by farnesol, a dephosphorylated intermediate of the mammalian mevalonate pathway. At micromolar concentrations, farnesol acts as a relatively non-discriminatory rapid open channel blocker of all types of high voltage-activated calcium channels, with a mild specificity for L-type channels. However, at 250 nM, farnesol induces an N-type channel-specific hyperpolarizing shift in channel availability that results in approximately 50% inhibition at a typical neuronal resting potential. Additional experiments demonstrated the presence of farnesol in the brain (rodents and humans) at physiologically relevant concentrations (100-800 pmol/g (wet weight)). Altogether, our results indicate that farnesol is a selective, high affinity inhibitor of N-type Ca(2+) channels and raise the possibility that endogenous farnesol and the mevalonate pathway are implicated in neurotransmitter release through regulation of presynaptic voltage-gated Ca(2+) channels.

Calcium Channel Blockers↗
PubMed2005

cDNA microarray analysis of differential gene expression in Candida albicans biofilm exposed to farnesol.

Candida albicans biofilms are structured microbial communities with high levels of drug resistance. Farnesol, a quorum-sensing molecule that inhibits hyphal formation in C. albicans, has been found to prevent biofilm formation by C. albicans. There is limited information, however, about the molecular mechanism of farnesol against biofilm formation. We used cDNA microarray analysis to identify the changes in the gene expression profile of a C. albicans biofilm inhibited by farnesol. Confocal scanning laser microscopy was used to visualize and confirm normal and farnesol-inhibited biofilms. A total of 274 genes were identified as responsive, with 104 genes up-regulated and 170 genes down-regulated. Independent reverse transcription-PCR analysis was used to confirm the important changes detected by microarray analysis. In addition to hyphal formation-associated genes (e.g., TUP1, CRK1, and PDE2), a number of other genes with roles related to drug resistance (e.g., FCR1 and PDR16), cell wall maintenance (e.g., CHT2 and CHT3), and iron transport (e.g., FTR2) were responsive, as were several genes encoding heat shock proteins (e.g., HSP70, HSP90, HSP104, CaMSI3, and SSA2). Further study of these differentially regulated genes is warranted to evaluate how they may be involved in C. albicans biofilm formation. Consistent with the down-regulation of the cell surface hydrophobicity-associated gene (CSH1), the water-hydrocarbon two-phase assay showed a decrease in cell surface hydrophobicity in the farnesol-treated group compared to that in the control group. Our data provide new insight into the molecular mechanism of farnesol against C. albicans biofilm formation.

Biofilms↗
PubMed2000

Farnesol modulates membrane currents in human retinal glial cells.

Farnesol, a C(15) natural isoprenoid, exerts complex modulating effects on the membrane permeability of human retinal glial (Müller) cells. Several glial cationic currents were examined. At low micromolar concentrations, farnesol reduced the amplitudes of all fast and depolarization-activated membrane currents expressed by Müller cells, that is, currents through 1) transient low-voltage-activated (LVA; IC(50) = 2.2 microM), 2) sustained high-voltage-activated Ca(2+) channels (HVA; IC(50) = 1.2 microM), 3) fast Na(+) channels (IC(50) = 9.0 microM), and 4) transient (A-type) K(+) channels (IC(50) = 4.7 microM). Furthermore, farnesol shifted the activation of LVA and HVA currents to more depolarized potentials by 21.3 +/- 7.4 mV and 8.3 +/- 4.5 mV, respectively. On the other hand, neither inwardly rectifying nor iberiotoxin-sensitive calcium-activated K(+) currents were affected by farnesol. Therefore, farnesol is assumed to be a biologically active substance that regulates ion channel activity in the glial cell membrane. Depressing rapid changes of the membrane potential and supporting a stable hyperpolarized status of the glial cells may enhance the efficiency of crucial glial functions such as extracellular K(+) clearance and neurotransmitter uptake.

Calcium Channel Blockers↗
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

The mevalonate/isoprenoid pathway inhibitor apomine (SR-45023A) is antiproliferative and induces apoptosis similar to farnesol.

Apomine (SR-45023A) is a new antineoplastic compound which is currently in clinical trials and representative of the family of cholesterol synthesis inhibitors 1,1-bisphosphonate esters. Apomine inhibits growth of a wide variety of tumor cell lines with IC(50) values ranging from 5 to 14 microM. The antiproliferative activity of apomine was studied in comparison with that of other inhibitors of the mevalonate/isoprenoid pathway of cholesterol synthesis, simvastatin, farnesol, and 25-hydroxycholesterol. All these compounds inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Apomine (IC(50) = 14 microM), simvastatin (IC(50) = 3 microM), farnesol (IC(50) = 60 microM), and 25-hydroxycholesterol (IC(50) = 2 microM) inhibited HL60 cell growth. Growth inhibition due to simvastatin was reverted by mevalonate, whereas the antiproliferative activity of apomine, farnesol, and 25-hydroxycholesterol was not. Apomine triggered apoptosis in HL60 cells in less than 2 h. Apomine and farnesol induced caspase-3 activity at concentrations similar to their IC(50) values for cell proliferation, whereas a 10-fold excess of simvastatin was necessary to trigger apoptosis compared to its potency on proliferation. Caspase-3 activity was not induced by 25-hydroxycholesterol. The overall similar profile on mevalonate synthesis inhibition, cell growth inhibition, and apoptosis suggests that apomine acts as a synthetic mimetic of farnesol.

Anticholesteremic Agents↗
PubMed1997

Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol.

Fruits and vegetables have protective effects against many human cancers, including pancreatic cancer. Isoprenoids are one class of phytochemicals which have antitumor activity, but little is known about their effects on cancer of the pancreas. We tested the hypothesis that isoprenoids would inhibit the growth of pancreatic tumor cells. Significant (60-90%) inhibition of the anchorage-independent growth of human MIA PaCa2 pancreatic tumor cells was attained with 25 microM farnesol, 25 microM geranylgeraniol, 100 microM perillyl amine, 100 microM geraniol, or 300 microM perillyl alcohol. We then tested the relative in vivo antitumor activities of dietary farnesol, geraniol, and perillyl alcohol against transplanted PC-1 hamster pancreatic adenocarcinomas. Syrian Golden hamsters fed geraniol or farnesol at 20 g/kg diet exhibited complete inhibition of PC-1 pancreatic tumor growth. Both farnesol and geraniol were more potent than perillyl alcohol, which inhibited tumor growth by 50% at 40 g/kg diet. Neither body weights nor plasma cholesterol levels of animals consuming isoprenoid diets were significantly different from those of pair-fed controls. Thus, farnesol, geraniol, and perillyl alcohol suppress pancreatic tumor growth without significantly affecting blood cholesterol levels. These dietary isoprenoids warrant further investigation for pancreatic cancer prevention and treatment.

Acyclic Monoterpenes↗
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↗
PubMed2005

Biologically active fluorescent farnesol analogs.

We describe ten polyene analogs of farnesol, typified by 3,7,11-trimethyl-2,4,6,8,10-dodecapentenaldehyde oxime, which preserve the length, cross-section, and approximate hydrophobicity of farnesol. Four of the ten display strong quorum-sensing activity in the human pathogen Candida albicans, with IC(50) values for inhibition of germ-tube formation as low as 10 microM. The polyenes display absorption maxima between 320 and 380 nm, with the extinction coefficients for the oximes approaching 100,000. All but two of the analogs are fluorescent, with excitation maxima varying over the range of 320-370 nm. Oxime anti-4, which can undergo fluorescence excitation at wavelengths beyond 400 nm, is demonstrated to be useful for confocal fluorescence microscopic imaging of fungal cells. The farnesol analogs are also expected to be useful for detection of farnesol binding proteins and in determination of farnesol pharmacokinetics.

Candida albicans↗
PubMed2002

Effects of apigenin and tt-farnesol on glucosyltransferase activity, biofilm viability and caries development in rats.

Propolis, a resinous hive product secreted by Apis mellifera bees, has been shown to reduce the incidence of dental caries in rats. Several compounds, mainly polyphenolics, have been identified in propolis. Apigenin and tt-farnesol demonstrated biological activity against mutans streptococci. We determined here their effects, alone or in combination, on glucosyltransferase activity, biofilm viability, and development of caries in rats. Sprague-Dawley rats were infected with Streptococcus sobrinus 6715 and treated topically twice daily as follows: (1) tt-farnesol, (2) apigenin, (3) vehicle control, (4) fluoride, (5) apigenin +tt-farnesol, and (6) chlorhexidine. Apigenin (1.33 mM) inhibited the activity of glucosyltransferases in solution (90-95%) and on the surface of saliva-coated hydroxyapatite beads (35-58%); it was devoid of antibacterial activity. tt-Farnesol (1.33 mM) showed modest antibacterial activity against biofilms and its effects on glucosyltransferases were minimal. The incidence of smooth-surface caries was significantly reduced by apigenin +tt-farnesol (60%), fluoride (70%), and chlorhexidine (72%) treatments compared to control (P < 0.05).

Analysis of Variance↗
PubMed2003

Farnesol biosynthesis in Candida albicans: cellular response to sterol inhibition by zaragozic acid B.

The dimorphic fungus Candida albicans produces farnesol as a quorum-sensing molecule that regulates cellular morphology. The biosynthetic origin of farnesol has been resolved by treating these cells with zaragozic acid B, a potent inhibitor of squalene synthase in the sterol biosynthetic pathway. Treatment with zaragozic acid B leads to an eightfold increase in the amount of farnesol produced by C. albicans. Furthermore, C. albicans cell extracts contain enzymatic activity to convert [(3)H]farnesyl pyrophosphate to [(3)H]farnesol. Many common antifungal antibiotics (e.g., zaragozic acids, azoles, and allylamines) target steps in sterol biosynthesis. We suggest that the fungicidal activity of zaragozic acid derives in large part from the accumulation of farnesol that accompanies the inhibition of sterol biosynthesis.

Antifungal Agents↗