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PubMed1996

Augmentation of epirubicin cytotoxicity by cycloheximide.

The effect of cycloheximide (CH) on the cytotoxic activity of the anthracycline antibiotic epirubicin (EPI) was examined in cell cultures of murine leukemia doxorubicin (DOX)-sensitive P388 and -resistant P388 cells. The addition of CH (0.002 mu g/ml) to the growth medium markedly enhanced the EPI-induced cytotoxic effect in sensitive cells as well as that observed in resistant cells. CH, however, did not affect the intracellular content of EPI. The inhibition of DNA synthesis in leukemia cells was remarkable with the combination of EPI and CH compared with each drug alone. These results suggest that the combination of EPI and CH appears to be useful in killing mouse leukemia cells.

Animals↗
PubMed1996

Increased heat shock protein 90 (hsp90) expression leads to increased apoptosis in the monoblastoid cell line U937 following induction with TNF-alpha and cycloheximide: a possible role in immunopathology.

In this study, we examined the hypothesis that heat shock proteins (hsp) (such as hsp72 and hsp90) are implicated in the regulation of forms of cell injury that lead to programmed cell death. The monoblastoid cell line U937 has been used as a model system. For hsp90, which is not heat inducible in this cell line, we used stable U937 transfectants that either hyperexpress or hypoexpress the protein. For hsp72 (which is reproducibly induced in all three cell lines to relatively high levels of expression), we studied U937 cells before and after heat shock. We showed that apoptosis does occur in the monoblast/mononuclear phagocyte lineage, and that it could be induced in vitro by serum deprivation, UV light, or TNF-alpha in combination with cycloheximide (cx). However, an excess of hsp90 is associated with increased apoptosis when the cells are treated with a combination of TNF-alpha and cx but not when they are exposed to UV B radiation. This was complemented by the finding that reduced hsp90 levels correlate with protection against apoptosis in the TNF-alpha- and cx-treated cells. Furthermore, new synthesis of hsp72 does not protect against apoptosis. Thus, hsp90 levels may play a role in controlling the part played by mononuclear phagocytes in immunopathology.

Antigens, CD↗
PubMed1977

Studies on tolerance. II. The effect of timing on inhibition of tolerance to morphine by cycloheximide.

Cycloheximide (CX) given 1 hour before each weekly dose of morphine inhibits the development of tolerance. The temporal relationship of the doses of CX and morphine sulfate seems to be a most important factor. CX (1 mg/kg s.c.) given 24 hours before, 6 hours before or 6 hours after weekly morphine injections (10 mg/kg s.c.) does not affect the rate or the degree of tolerance development. The inhibition of tolerance seen after weekly administration of CX plus injections of morphine is not seen until several weeks after drug treatment has begun and the difference between the morphine only and the morphine plus CX groups persists for a number of weeks after drug treatment has been terminated. The inhibition of tolerance seen after CX does not appear to be due to any nonspecific debilitating effect of CX. However, it may be related to the ability of CX to suppress protein synthesis. The identity of the proteins involved or how they are involved in the tolerance phenomenon remains unclear.

Analgesia↗
PubMed1997

Cycloheximide phase-shifts, but does not prevent, de novo Krox-24 protein expression.

Previous studies show that focal hippocampal injury transiently increases NMDA receptor-dependent expression of inducible transcription factors (ITFs including Krox-24) in rat dentate gyrus neurons. Furthermore, pretreatment with the protein synthesis inhibitor, cycloheximide (CHX), prevents de novo ITF protein expression 1 h post-injury. Here, we further characterize the effects of a single pretreatment dose of CHX on injury-induced expression of Krox-24 and show that CHX pretreatment phase-shifts (delays), but does not prevent, de novo expression of Krox-24 in hippocampal dentate gyrus neurons following injury. This may have implications for studies which use CHX pretreatment to examine the role of gene expression and de novo protein synthesis in long-term memory formation, the stabilization of long-term potentiation, kindling and neuronal injury.

Animals↗
PubMed1998

Sustained phosphorylation of cytosolic phospholipase A2 accompanies cycloheximide- and adenovirus-induced susceptibility to TNF.

In this report we examine the phosphorylation state of cytosolic phospholipase A2 (cPLA2) in C3HA fibroblasts that have been treated with TNF, cycloheximide (CHI), or a combination of both compounds. Our experiments show that TNF and CHI, when used independently, caused the rapid phosphorylation of cPLA2 (within 10 min). In both cases, cPLA2 was subsequently dephosphorylated to pretreatment levels by 40 min. In addition, under these conditions [3H]arachidonic acid was not released, and we could not detect a change in the activity of cPLA2 in vitro. In contrast, in cells treated with a combination of TNF and CHI, we found that the dephosphorylation of cPLA2 was inhibited, and cPLA2 remained phosphorylated for up to 2 h. In vitro we found that sustained phosphorylation of cPLA2 was accompanied by a 60 to 80% increase in the activity of cPLA2. The sustained phosphorylation of cPLA2 also occurred in cells infected with the adenovirus mutant dl309, suggesting that sustained phosphorylation may be a general requirement for the activation of cPLA2 in apoptotic cells. We also found that sustained phosphorylation of phosphoproteins is not a general consequence of apoptotic death, since the phosphorylation of p42 mitogen-activated protein kinase was not sustained. Finally, we show that the phosphatase inhibitor orthovanadate acts as does CHI to render cells susceptible to TNF, suggesting that resistance to TNF may depend on TNF's ability to induce the expression of tyrosine or dual specificity phosphatase(s).

3T3 Cells↗
PubMed1987

Serum-induced G0/G1 transition in chemically transformed 3T3 cells. Independence of protein synthesis, stable "memory", and enhancement by cycloheximide pretreatment.

Quiescent, chemically transformed (benzo-alpha-pyrene) BALB/c 3T3 cells (BP A31) enter the cell division cycle when exposed to complete medium containing 10% fetal calf serum (FCS); the number of cells recruited is a function of the duration of serum exposure. The recruitment of cells by short (less than 4 h) serum pulses is not inhibited by simultaneous exposure to cycloheximide (CH), and therefore the initial commitment does not require protein synthesis. The cells enter S phase with a constant delay following the removal of CH, even if CH exposure has been continued for as long as 20 h after the end of the serum pulse. The cell recruitment by serum pulses was inhibited by 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), an inhibitor of cytoplasmic mRNA accumulation. These data suggest that serum exposure produces a stable 'memory' that is necessary and sufficient for the eventual progression through G1 to S phase that occurs when protein synthesis is resumed after the removal of CH; this 'memory' probably consists of mRNA species that are induced by serum and that are stable in the absence of protein synthesis. Unexpectedly, pretreatment of quiescent BP A31 cells with CH (8-24 h) dramatically increased the fraction of the total cell population that is recruited by a serum pulse of fixed duration.

Animals↗
PubMed1997

Developmental capacity of bovine oocytes following inhibition of meiotic resumption by cycloheximide or 6-dimethylaminopurine.

This study was conducted to assess the fertilizability and developmental capacity of bovine oocytes which had been maintained in meiotic arrest by either a protein synthesis inhibitor, cycloheximide (CHX), or an inhibitor of serine/threonine protein kinases, 6-dimethylaminopurine (6-DMAP). Both CHX and 6-DMAP reversibly prevented nuclear maturation of nearly all oocytes for 24 h. After the reversal of arrest, CHX-treated oocytes could be successfully matured and fertilized. They developed to the blastocyst stage at slightly lower rates than oocytes cultured without inhibition for 22 h prior to sperm addition but at higher rates than those incubated in a medium containing no inhibitors for 46 h prior to fertilization. Oocytes inhibited by CHX for 48 h matured and fertilized normally but failed to develop into blastocysts. Even though 6-DMAP-treated oocytes completed meiosis I after removal from the drug, the rates of fertilization and blastocyst formation were lower than for untreated oocytes or CHX-treated oocytes. Effects of adding FSH and/or estradiol-17 beta (E(2)) during CHX-inhibition for 24 h were also examined. Embryos from oocytes treated with CHX and E(2) or with CHX and FSH + E(2) developed into blastocysts at similar rates as the controls. Further development of inhibited oocytes was examined by transferring blastocysts derived from oocytes inhibited by CHX with FSH and E(2) for 24 h to recipient heifers. Two calves were obtained following transfer. These results indicate that CHX-inhibited oocytes retain developmental competence, while 6-DMAP-inhibited oocytes after the reversal of arrest have reduced capacities for fertilization and further development. The addition of FSH and E(2) during CHX-inhibition improves development to the blastocyst stage of the oocytes that are capable of initiating and maintaining pregnancy after embryo transfer to recipient animals.

Journal Article↗
PubMed1997

Persistence of cadmium-induced adaptive response to genotoxicity of maleic hydrazide and methyl mercuric chloride in root meristem cells of Allium cepa L.: differential inhibition by cycloheximide and buthionine sulfoximine.

With an objective to determine the period of persistence of the metal-induced adaptive response to chemical mutagens and heavy metals, growing root meristems of Allium cepa were conditioned by cadmium sulfate (CdSO4), 4 x 10(-7) and 4 x 10(-6) M for 1 h and subsequently challenged by maleic hydrazide (MH), 5 x 10(-3) M or methyl mercuric chloride (MMCl), 1.26 x 10(-6) M for 3 h at different time intervals ranging from a few minutes to several hours following the conditioning dose. Root meristems, fixed at regular intervals during recovery from 6 to 48 h, were cytologically analysed for cells with micronuclei (MNC). The adaptive responses to MH and MMCl were observed as early as 5 min after the Cd-conditioning that persisted for at least 48 h. Metabolic inhibitors, cycloheximide (CH). 10(-7) M and buthionine sulfoximine (BSO), 10(-4) M administered either prior to or simultaneous with Cd-conditioning effectively prevented the adaptive response to MH. Whereas BSO, an inhibitor of phytochelatin synthesis, prevented the adaptive responses from 15 min to 8 h after the conditioning dose, CH an inhibitor of cytoplasmic protein synthesis prevented the same from 6 to 48 h. The findings underscored the differential roles of phytochelatins and proteins underlying the foregone metallo-adaptive response.

Acclimatization↗
PubMed1997

Anti-apoptotic actions of cycloheximide: blockade of programmed cell death or induction of programmed cell life?

Cycloheximide (CHX), long recognized for its ability to inhibit protein synthesis, has been widely employed in studies of cell death to the extent that prevention of cell death by CHX has been used as prima facie evidence for a subtype of apoptosis called 'programmed cell death'. However, very rarely have investigators determined the effects of CHX on protein synthesis in their particular cell death paradigms. Recent findings are revealing alternative mechanisms of action of CHX that involve, ironically, stimulation of cytoprotective signalling pathways. For example, in embryonic rat hippocampal cell cultures CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including Bcl-2. CHX induces increases in immediate early gene mRNA levels, and can activate several different kinases and transcription factors that are also activated by various insults and in response to anti-apoptotic growth factors. Concentrations of CHX that cause only a modest and/or transient decrease in over-all protein synthesis may prevent cell death by inducing cytoprotective signalling pathways ('programmed cell life'), whereas higher concentrations of CHX may prevent cell death by blocking the expression of 'death genes'. Establishing which of these anti-apoptotic mechanisms of action of CHX is operative in each cell death paradigm is clearly essential for proper interpretation of experimental results.

Journal Article↗
PubMed1997

Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by TNF plus cycloheximide in U937 cells.

U937 human myeloid leukemia cells are induced to apoptosis by tumour necrosis factor (TNF) plus cycloheximide (CHX). We have analysed the effect of various inhibitors of the arachidonic acid (AA) metabolism on several features of this process. The formation of high molecular weight and oligonucleosomal DNA fragments as well as nuclear fragmentation were reduced by inhibitors of 5-lipoxygenase (BWA4C and BWB70C), 5-LO activating protein (MK-886), and cytosolic PLA2 (AACOCF3). None of these agents blocked the morphological changes detected by microscopy or flow cytometry, phosphatidylserine exposure on the cell surface or Caspase 3-like activation. AA also induced nuclear fragmentation at a concentration of 1-20 microM. However, the mechanisms by which these inhibitors act, remain unexplained since there was no 5-LO expression in the U937 cells and no AA release followed their stimulation with TNF plus CHX.

Journal Article↗
PubMed1994

Loss of Microtubules in the Interphase Cells of Onion (Allium cepa L.) Root Tips from the Cell Cortex and Their Appearance in the Cytoplasm after Treatment with Cycloheximide.

As part of a project to investigate the mechanism of cortical microtubule (MT) alignment, we examined the effects of cycloheximide (CHM) on cortical MTs in the root tip cells of Allium cepa L. Results show that although a preprophase band of MTs remained in the cell cortex, interphase MTs disappeared from the cortical cytoplasm and then appeared concomitantly in the inner cytoplasm when the rate of de novo protein synthesis was reduced with CHM (11-360 [mu]M for 2 h)

Journal Article↗
PubMed1972

Protein synthesis by isolated etioplasts and chloroplasts from pea and wheat and the effects of chloramphenicol and cycloheximide.

Etioplasts capable of incorporating (14)C-leucine into protein have been isolated from dark-grown pea and wheat plants. The requirements for leucine incorporation for etioplasts were similar to those for chloroplasts. An ATP-generating system, Mg(2+), and GTP were required. The amino-acid-incorporation activity of etioplasts from wheat was comparable to that of chloroplasts on an RNA basis, whereas the activity of pea etioplasts was about 50% of the activity of pea chloroplasts. The incorporation of leucine into protein by etioplasts and chloroplasts from pea and wheat was inhibited by chloramphenicol, and to a slight extent by cycloheximide.

Journal Article↗
PubMed1972

l-Phenylalanine Ammonia-lyase (Maize): Partial Purification and Response to Gibberellic Acid and Cycloheximide of l-Phenylalanine and l-Tyrosine Ammonia-lyase Activities.

Extracts of maize leaf sheath tissue deaminate both l-phenylalanine and l-tyrosine. The activities with both substrates are enhanced by treating the plant with gibberellic acid. Both activities decrease rapidly at the same rate when tissue is incubated in a moist atmosphere, and this decrease can be slowed by treatment with cycloheximide. The ratio of the activities was constant throughout a series of purification steps which included acetone and ammonium sulfate precipitation, and passage through an agarose column. The two activities could not be separated by isoelectric focusing. These results support our earlier conclusion that both activities occur at the same catalytic site.

Journal Article↗
PubMed1977

Effects of cycloheximide and chloramphenicol on the synthesis of polypeptides found in three subcellular fractions of maize scutellum.

The effects of two protein synthesis inhibitors, cycloheximide and chloramphenicol, on the synthesis of mitochondrial proteins in maize (Zea mays) have been studied. The results of these investigations suggest that while most of the mitochondrial proteins are synthesized in the cytoplasm and are subsequently associated with the mitochondrion, several proteins of the mitochondrial inner membrane are synthesized within the mitochondrion. These results are consistent with those observed in several other systems, but not previously reported for higher plants.

Journal Article↗
PubMed1986

The effects of benzyladenine, cycloheximide, and cordycepin on wilting-induced abscisic Acid and proline accumulations and abscisic Acid- and salt-induced proline accumulation in barley leaves.

Benzyladenine inhibits proline accumulation in wilted, abscisic acid (ABA)-treated, and salt-shocked barley leaves. It does not affect ABA accumulation or disappearance in wilted leaves. Inhibition of proline accumulation in salt-shocked leaves was observed both when benzyladenine was added at the beginning of or after salt treatment. Cycloheximide (CHX) and cordycepin inhibited both ABA and proline accumulations in wilted barley leaves and proline accumulation in ABA-treated leaves. In salt-shocked leaves, cordycepin inhibited proline accumulation when added after salt treatment but before proline began to accumulate but not when added after the onset of proline accumulation. CHX delayed the accumulation of proline in salt-shocked leaves but, after a period of time, proline accumulated in the CHX-treated leaves at rates comparable to the salt-treated control. This delay and subsequent accumulation was observed when CHX was added before, during, and after salt treatment. However, the earlier in the salt treatment period that CHX was given, the longer was the observed delay. These results are interpreted to indicate that gene activation is involved in proline accumulation in response to wilting, to ABA, and to salt in barley leaves. This gene activation is in addition to the gene activation that is required for ABA accumulation in wilted leaves. If ABA accumulation is required for proline accumulation in wilted barley leaves, then two sets of gene activation are involved in wilting-induced proline accumulation. All of our results are consistent with this possibility but do not prove it. The inhibition of proline accumulation by benzyladenine is probably neither due to an effect on gene activation nor to an effect on the ABA level.

Journal Article↗
PubMed1992

Cycloheximide Reduces the Effects of Anoxic Insult In Vivo and In Vitro.

In vivo and in vitro techniques were utilized to examine the influence of a protein synthesis blocker, cycloheximide (CHX), on the damaging effects of anoxia in the rat. CHX administered 1 h before transient (30 min) forebrain ischaemia increased the survival of animals, decreased body weight loss and reduced the occurrence of delayed degeneration in the CA1 pyramidal region. The same dose of CHX injected 1 h after ischaemia induced status epilepticus, a decrease in survival rate, and did not reduce weight loss or CA1 damage in any of the surviving rats. Electrophysiological techniques were then used to determine the effects of various periods of anoxia and aglycaemia (AA) on CA1 field excitatory postsynaptic potentials (EPSPs) in hippocampal slices incubated in the presence or absence of CHX. In CHX-treated slices, recuperation of EPSP amplitude (45 +/- 16%) was significantly greater than in control slices (9 +/- 9%) following an AA episode of 3 min 45 s. No difference was seen in the percent recuperation of EPSPs in the control and CHX-treated slices after shorter or longer episodes of AA. From these studies, it appears that CHX protects against the damaging effect of ischaemia in vivo or AA in vitro.

Journal Article↗
PubMed1999

Physiological responses of Tetrahymena pyriformis to copper, zinc, cycloheximide and Triton X-100.

Protozoa, and particularly ciliates, are essential in aerobic purification processes of wastewaters and have proved to be very sensitive to environmental changes. The physiological response of the ciliate Tetrahymena pyriformis was assessed in terms of mortality, growth and grazing capacity after exposure to four toxicants: copper, zinc, cycloheximide and Triton X-100. In the ranges of concentrations used, mortality, inhibition of growth and inhibition of grazing were observed with all toxicants employed, but in different ways. Copper and zinc showed lower toxicity than observed in other studies with protozoa, though some of the present results are in accordance with those reported by other authors. This supports the importance of the organism tested and the experimental conditions of the bioassays.

Journal Article↗