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PubMed1990

Cycloheximide-induced modulation of TNF-mediated cytotoxicity in sensitive and resistant ovarian tumor cells.

The mechanism of sensitivity and resistance of various ovarian carcinoma lines to recombinant tumor necrosis factor (rTNF)-mediated cytotoxicity has been investigated using a 24-h 51Cr-release assay. The cell line PA-1 is sensitive to TNF in a dose-dependent manner, whereas the cell line SKOV-3 is resistant to TNF even at high concentrations. The simultaneous addition of TNF and cycloheximide (CHX) in the assay converted the resistant SKOV-3 line into a sensitive line, but no detectable change was observed with PA-1. rTNF inhibited DNA, RNA, and protein synthesis of the sensitive PA-1 line, whereas it had no effect on SKOV-3. This finding was not due to differences in the expression of TNF receptors, as both cell lines expressed equivalent numbers of receptors. The addition of CHX to TNF resulted in suppression of DNA, RNA, and protein synthesis in both the sensitive and the resistant cell lines. Pretreatment of the cell line with TNF for 3 h and subsequent washing resulted in significant cytotoxicity of the sensitive PA-1 line and some cytotoxicity against SKOV-3. However, if the cells were pretreated with CHX for 3 h followed by rTNF for 24 h, a significant decrease in cytotoxicity was observed in both cell lines. Under these conditions, there was no significant inhibition of DNA, RNA, or protein synthesis. Pretreatment of cells for 24 h with TNF and 24 h with CHX resulted in augmentation of the cytotoxicity of PA-1 and SKOV-3, whereas pretreatment for 24 h with CHX followed by 24 h with TNF resulted in no cytotoxicity. Cells pretreated with CHX for 24 h showed poor binding of [125]I-TNF and poor internalization, whereas cells pretreated for 24 h with TNF showed marked enhancement of internalization. The sensitivity of freshly derived ovarian carcinoma lines to TNF and CHX demonstrated that TNF-resistant cells became more sensitive if treated with CHX. These results demonstrate the potential use of metabolic inhibitors in increasing the sensitivity of fresh ovarian tumor cells to TNF.

Cell Survival↗
PubMed1998

The prevention of fatalities in cycloheximide challenged mice pretreated with a submicrogram dose of lipopolysaccharide or with a small volume of cell-free Ehrlich ascites tumour fluid.

OBJECTIVE AND DESIGN: Therapeutic strategies were employed to better understand the pathogenesis of fatal cycloheximide (CX) intolerance in mice pretreated with a submicrogram dose of lipopolysaccharide (LPS) or with a small volume of cell-free Ehrlich ascites tumour fluid (EAF). MATERIALS AND SUBJECTS: Inbred, male CBA-strain mice. METHODS: Aminoguanidine (AMG), a selective inhibitor of inducible nitric oxide synthase (iNOS) was used to determine the role of nitric oxide (NO) in the fatalities. Dexamethasone (DEX) or nordihydroguaiaretic acid (NDGA) were used to assess possible involvement of tumour necrosis factor-alpha (TNF) in sensitisation to CX. RESULTS: AMG protected CX challenged mice pretreated with LPS or with EAF. DEX, but not NDGA, protected the former animals; both DEX and NDGA protected the latter. CONCLUSION: AMG protection indicates the essential role of iNOS in CX-precipitated fatalities. It is suggested that the pretreatments either directly or indirectly place iNOS expression under control of a labile protein repressor. In the case of EAF pretreated mice, a role for TNF could not be excluded, whereas in LPS pretreated animals TNF plays no part in sensitising to CX.

Animals↗
PubMed2004

beta2-integrins mediate a novel form of chemoresistance in cycloheximide-induced U937 apoptosis.

In this study with cycloheximide (CHX, an inhibitor of protein synthesis) and the human leukaemic cell line U937, a novel form of chemoresistance, which we termed sudden drug resistance (SDR), was identified using Hoechst33258 staining, Western blot and DNA Ladder. CHXhigh (10-100 microg/ml)-induced apoptosis can spontaneously subside after 4-6 h or can be inhibited by short-term preincubation with CHXlow (2.5 microg/ml). Unlike typical multidrug resistance, SDR is not caused by reduced drug accumulation or altered protein expression, and may be associated with a non-P-glycoprotein mechanism. To uncover this underlying mechanism, we focused on U937 cell aggregation promoted by CHX, because cell adhesion has been suggested to influence cell survival and prevent apoptosis. EDTA, or anti-CD18 monoclonal antibody, but not EGTA, acetylsalicylic acid or RGDS tetrapeptide, abrogated this homotypic aggregation and greatly increased CHX-induced apoptosis in a time-dependent manner, while fibrinogen and soluble intercellular adhesion molecule-1 exerted opposite effects. These results establish that beta2-integrin engagement is a key mediator of SDR, although it may be non-exclusive. This finding supplements the classical basis of chemoresistance and may provide another opportunity for improved leukemia therapy.

Apoptosis↗
PubMed2003

Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by, but not dependent on, adrenal hormones.

RATIONALE: AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to improve memory in both animals and humans. In animals, adrenal hormones modulate the efficacy of many memory-enhancing compounds, including piracetam and tacrine (Cognex). OBJECTIVE: To investigate the role of adrenal hormones in the memory-enhancing action of AIT-082. METHODS: Plasma levels of adrenal hormones (corticosterone and aldosterone) in mice were significantly reduced by surgical or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral administration of corticosterone. The effects of these hormone level manipulations on the memory-enhancing activity of AIT-082 and piracetam were evaluated using a cycloheximide-induced amnesia/passive avoidance model. RESULTS: As previously reported by others, the memory enhancing action of piracetam was abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT-082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP) that did not improve memory in control animals did improve memory in adrenalectomized animals. These data suggested that, similar to piracetam and tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the activity of AIT-082. CONCLUSIONS: These data suggest that while AIT-082 function is not dependent on adrenal hormones, it is modulated by them. That memory enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may have positive implications for its clinical utility, given that many Alzheimer's disease patients have elevated plasma cortisol levels.

Adrenalectomy↗
PubMed2001

Cycloheximide resistance conferred by novel mutations in ribosomal protein L41 of Chlamydomonas reinhardtii.

Although most eukaryotic cells are sensitive to the 80S ribosome inhibitor cycloheximide (CYH), naturally occurring CYH resistance is widespread amongst yeast species. The primary determinant of resistance appears to be a single residue within ribosomal protein L41; resistance is acquired by the substitution of a conserved proline (P56) by a glutamate residue. We have isolated the L41 gene (RPL41) from the green alga Chlamydomonas reinhardtii, and investigated the molecular basis of CYH resistance in various mutant strains. In both the wild-type strain and the mutant act-1, a proline is found at the key position in L41. However, analysis of six independently isolated act-2 mutants reveals that all have point mutations that replace the proline with either leucine or serine. Of the two changes, the leucine mutation confers significantly higher levels of CYH resistance. This work identifies the ACT-2 locus as RPL41 and provides a possible dominant marker for nuclear transformation of C. reinhardtii.

Amino Acid Sequence↗
PubMed2000

Okadaic acid induces cycloheximide and caspase sensitive apoptosis in immature neurons.

Previous studies have shown that okadaic acid (OA) evokes tau phosphorylation and neurofibrillary changes in vivo, and in cultured neurons, that resemble Alzheimer's disease pathogenesis. In order to investigate the mechanism of OA-neurotoxicity, we treated cultured rat neurons with OA and examined nuclear morphology, phosphatidylserine (PS) externalization, alpha-fodrin cleavage, and the effects of cell death inhibitors. Our results demonstrated that cycloheximide (CHX) and the broad-spectrum caspase inhibitor, ZVAD, significantly reduced cell death in a dose-dependent manner. Nuclear fragmentation, a hallmark of apoptosis, occurred after OA treatment and was inhibited by CHX or ZVAD. PS externalization was apparent in 6-12 h in neurites and in cell bodies, and peaked at 24 h after OA treatment. Cleavage of alpha-fodrin as visualized by the appearance of 150- and 120-kDa bands appeared with a time course similar to PS externalization. These results suggest that OA induce CHX and caspase sensitive neuronal apoptosis.

Amino Acid Chloromethyl Ketones↗
PubMed1984

Isolation of highly purified Golgi membranes from rat liver. Use of cycloheximide in vivo to remove Golgi contents.

Following administration of cycloheximide to rats in order to deplete the liver of secretory products, Golgi membranes have been isolated largely free of internal contents. These membranes have a high specific activity of galactosyltransferase (400 times that of the homogenate) and are thought to be derived from the trans Golgi. Their phospholipid and polypeptide composition resembles that of Golgi membranes prepared by other procedures but their triacylglycerol and cholesterol contents are greatly reduced. These results conflict with previous reports that trans Golgi membranes are rich in cholesterol.

Albumins↗
PubMed1975

Effects of colchicine and cycloheximide on the functional and non-functional lipoprotein lipase fractions of rat heart.

In response to food deprivation, total myocardial lipoprotein lipase activity increased gradually over a period of 9 h. Although lipoprotein lipase exists in a functional and non-functional form in the myocardium, most of the increas in activity occurred in the functional (heparin-releasable) lipoprotein lipase fraction. The administration of colchicine, while having no effect on the increase seen in total lipoprotein lipase activity, did inhibit the increase in the functional fraction, while at the same time, caused a marked rise in the activity of the non-functional (non-releasable) fraction. In rats injected with colchicine after a 24-h fast, total lipoprotein lipase activity was not affected, but activity levels in the functional fraction declined while that in the non-functional fraction increased. These results suggest that the functional lipoprotein lipase is constantly being formed in sites not readily accessible to heparin (presumably the myocardial cells) and transported to its site of action, the surface of the endothelial cells of the capillaries. Cycloheximide administration to rats starved for 24 h caused a decline in activity in both the functional (half-life of about 2 h) and the non-functional (half-life of about 4 h) lipoprotein lipase fractions. These results suggest that the functional and non-functional lipoprotein lipase fractions may correspond to two distinct enzyme species.

Animals↗
PubMed1981

Effects of dibutyryl cyclic AMP and theophylline on rat pancreatic phospholipids in vitro. Ca2+-sensitive decrease in phosphatidylinositol and cycloheximide-sensitive increase in phosphatidic acid.

We evaluated the effects of dibutyryl cyclic AMP and theophylline on rat pancreatic phospholipid metabolism in vitro. Dibutyryl cyclic AMP decreased mean phosphatidylinositol concentration by 30%, increased phosphatidic acid and phosphatidylglycerol concentrations by 90 and 25%, respectively, and increased [32P]phosphate incorporation into phosphatidic acid and phosphatidylinositol several-fold. Theophylline provoked similar changes in phosphatidic acid and phosphatidylinositol concentrations, and both stimulatory agents enhanced amylase and insulin secretion. Effects of dibutyryl cyclic AMP on amylase secretion and phospholipid levels were dependent on Ca2+. Cycloheximide blocked induced increases in phosphatidic acid, but did not diminish phosphatidylinositol breakdown or amylase secretion. Contrary to previous postulations, the present findings suggest: (a) cyclic AMP provokes large-scale phosphatidylinositol breakdown in the pancreas; (b) this phosphatidylinositol breakdown is dependent on Ca2+; and (c) phosphatidylinositol breakdown may contribute to exocytosis. In addition, it appears that a labile protein is required for synthesis of phosphatidic acid from 1,2-diacylglycerol and ATP.

Animals↗
PubMed1985

Stimulation of prostaglandin E2 production by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters in macrophages and its inhibition by cycloheximide.

The effects of TPA (12-O-tetradecanoylphorbol 13-acetate)-type and non-TPA-type tumor promoters on prostaglandin E2 production by peritoneal macrophages of rats were examined. Among the TPA-type tumor promoters, aplysiatoxin was most potent in stimulating prostaglandin E2 production followed by dihydroteleocidin B, teleocidin, TPA and debromoaplysiatoxin. Prostaglandin E2 production by aplysiatoxin treatment was stimulated at doses up to 0.1 ng/ml. Palytoxin, a non-TPA-type tumor promoter, also stimulated both prostaglandin E2 production and the release of radioactivity from [3H]arachidonic acid-labeled macrophages. However, the dose required for the expression of these effects by palytoxin was up to 3 pg/ml. It was suggested that the tumor promoters are associated with the activity to stimulate arachidonic acid metabolism, irrespective of their type. Cycloheximide, a protein synthesis inhibitor, inhibited both prostaglandin E2 production and the release of radioactivity from prelabeled macrophages stimulated either by the TPA-type tumor promoters or by the non-TPA-type tumor promoter. It is possible that the tumor promoters may induce the synthesis of some proteins responsible for the stimulation of arachidonate metabolism.

Acrylamides↗
PubMed1984

Inhibition of polyriboinosinic:polyribocytidylic acid-induced depression of mouse hepatic mixed function oxidases by actinomycin D or cycloheximide.

Administration of a single dose of the potent interferon inducer poly rI:rC to Swiss Webster mice depressed hepatic cytochrome P-450 to 75% of control, ethylmorphine N-demethylase to 56% of control and DMN N- demethylases I and II to about 80% of control. Although each enzyme responded in a unique manner, maximum depression occurred at 24 hours after poly rI:rC administration and the concurrent administration of inhibitors of protein synthesis (actinomycin D or cycloheximide) prevented this depression. These data suggest that poly rI:rC effects on the mixed function oxidases are not species specific although depression follows a time course shorter than that reported in the rat (maximum depression at 40 hours after poly rI:rC administration) and that depression occurs through the stimulation of a protein responsible for degrading cytochrome P-450.

Animals↗
PubMed1986

Destabilization of cytoplasmic mouse mammary tumor RNA by heat shock: prevention by cycloheximide pretreatment.

Thermal stress of cultured mouse mammary carcinoma cells results in a rapid loss of basal and glucocorticoid-stimulated mouse mammary tumor virus (MMTV) RNA. MMTV RNA is almost nondetectable within 1-2 hr after a shift in the culture temperature to 42 degrees. Actin mRNA is stable over this time period. Pretreatment of the cells with cycloheximide prevents the decay of MMTV RNA. Nuclear associated glucocorticoid receptor is not decreased but rather increased about 95% by the heat shock. The results show that heat shock has pronounced effects on expression of a glucocorticoid-regulated gene, and suggest that a nuclease, which is subject to rapid turnover, is stimulated by thermal stress.

Animals↗
PubMed1989

Transient increase in the c-fos mRNA level after change of culture condition from serum absence to serum presence and after cycloheximide addition in rat 3Y1 fibroblasts.

When 3Y1 cells resting at a saturation density were mitotically stimulated with serum, the c-fos mRNA level markedly increased in a short period of time and then decreased rapidly to an undetectable level. Subsequent serum deprivation followed by serum re-addition or subsequent cycloheximide addition caused a transient re-increase in the c-fos mRNA level. These results can be explained by assuming that the continuous expression of the c-fos gene at a minimum level is necessary for the eventual initiation of S phase, and that the over-expression of the c-fos gene occurs when the control of the gene expression is transiently disturbed by the change of the culture condition.

Animals↗
PubMed1987

The effect of chloramphenicol and cycloheximide on platelet aggregation and protein synthesis.

This study investigated the role of platelet protein synthesis in platelet aggregation. Cycloheximide (Cx) and chloramphenicol (Cm) were used as inhibitors of cytoplasmic (80S ribosome directed) and mitochondrial protein synthesis respectively. The effect of these agents on human platelet aggregation and L-[U-14C]leucine incorporation into platelet protein was investigated. Cm exhibited dose-dependent inhibition of collagen, thrombin and secondary ADP aggregatory responses, but had no effect on arachidonate or primary ADP responses over a similar concentration range (3.1 X 10(-3), 3.1 X 10(-4) and 3.1 X 10(-5) M). Cm also inhibited platelet secretion associated with collagen and secondary ADP responses. Furthermore, Cm exhibited a similar dose-dependent inhibition of L-[U-14C]leucine incorporation into platelet protein reaching 80% inhibition of incorporation at 3 X 10(-3) M. At similar concentrations (3.5 X 10(-3), 3.5 X 10(-4) and 3.5 X 10(-5) M) Cx failed to show inhibition of human platelet aggregation by all agonists used with the exception of collagen where some inhibition was seen at high Cx concentration (3.5 X 10(-3) M). Cx was also found to be ineffective at inhibiting L-[U-14C]leucine incorporation into platelet protein at all concentrations tested. These results suggest that the majority of platelet protein synthesis is mitochondrial and that this protein synthesis may have a role in human platelet aggregation.

Blood Platelets↗
PubMed1992

Differential turnover of enzymes involved in human monocyte eicosanoid metabolism. Selective inhibition of cyclooxygenase product formation by cycloheximide in the absence of effects on 5-lipoxygenase or phospholipase A2.

Human monocytes treated with cycloheximide (CHX) demonstrated a concentration- and time-dependent inhibition of prostaglandin E2 (PGE2) synthesis and release in response to stimulation with phorbol myristate acetate, ionomycin, serum-treated zymosan, or concanavalin A. The effect of CHX required preincubation and was largely reversible within 2 hr. Thromboxane A2 release was affected similarly but no comparable effects were observed on labeled arachidonic acid release or leukotriene B4 generation. The PGE2 response was also inhibited by CHX when monocytes were given exogenous arachidonic acid with or without stimulation. CHX pretreatment also comparably decreased the amount of immunoreactive cyclooxygenase in resting and stimulated monocytes. These data indicate that monocyte cyclooxygenase, in contrast to phospholipase A2 or 5-lipoxygenase and their regulatory proteins, turns over rapidly and may be a target for up- or down-regulation by pharmacologic or (potentially) physiologic agents which affect protein synthesis or degradation.

Arachidonate 5-Lipoxygenase↗
PubMed1992

Abrogation of adriamycin toxicity in vivo by cycloheximide.

The processes involved in cell killing by Adriamycin (ADR) and other agents that interact with topoisomerase II are unclear. To investigate the mode of ADR cytotoxicity in vivo, we have investigated the effects of the protein synthesis inhibitor, cycloheximide (CH), on cell killing by ADR in the murine intestinal tract. We have used morphological criteria to assay the cell death. ADR rapidly induces cell death in this tissue that has the morphology of apoptosis or programmed cell death. CH, when administered immediately after ADR, reduced the incidence of cell death by approximately 81% at 3 hr and approximately 51% at 6 hr after treatment. The inhibitor was only effective when administered within 0.5 hr of ADR suggesting that critical events leading to cell death may occur during this period. The inhibitor did not interfere with the ADR uptake or retention. Significant positive correlation was observed between protein and DNA synthesis inhibition (as measured by precursor uptake) and apoptosis inhibition. CH delayed progression of cells through all phases of the cell cycle except mitosis. However, ADR also had a similar effect, suggesting that progression through the cell cycle is not necessary for the expression of apoptosis. The effectiveness of CH in apoptosis inhibition, even when administered 0.5 hr after the ADR, coupled with the rapid uptake of ADR by the intestinal epithelium suggests that the mode of inhibition is unlikely to be modulation of cellular targets of ADR such as topoisomerase II or inhibition of formation of ADR-topoisomerase II complex. These data indicate that topoisomerase II-interacting agents such as ADR may induce apoptosis; the processes leading to cell death in this situation are thought to be gene dependent and require protein synthesis for their expression. Thus, the cytoprotective effect of CH may be due directly to the inhibition of protein synthesis.

Animals↗
PubMed1981

Cycloheximide activation of the lordotic response in low-dose, estrogen-treated ovariectomized rats: evidence for modulating inhibitory influences of the limbic system on sexual behavior.

This study tested the effect on intracranially injected cycloheximide (CHX), an inhibitor of protein synthesis, on facilitation of sexual receptivity in ovariectomized rats. The rats received 0.5 microgram estradiol benzoate (EB), s.c. once daily on days 8 through 12 after ovariectomy (OVX). Either CHX (in 0.5 microliter saline) or 0.5 microliter saline was injected into the lateral septum (LS), cortical nucleus (ACO) or medial nucleus of the amygdala or medial preoptic area on day 11 after OVX. The dose of EB was insufficient to facilitate lordotic behavior on day 10 or day 12 after OVX unless CHX was injected into the LS or ACO. Injection of saline did not influence lordosis.

Animals↗
PubMed1981

A quantitative regional analysis of protein synthesis inhibition in the rat brain following localized injection of cycloheximide.

Previous work has shown that bilateral injection of as little as 10 microgram of cycloheximide (CHX) into the amygdala, but not into the internal capsule, caused a time-dependent disruption of long-term retention of passive avoidance training. Under these conditions, protein synthesis in the entire brain was inhibited by less than 10%. The present study was undertaken to quantify the resulting inhibition of protein synthesis in various brain regions (amygdala, internal capsule, caudate, cortex, hippocampus, thalamus, hypothalamus and the entire half brain). Rats were subcutaneously injected with L-[14C-methyl]methionine following unilateral administration of CHX via a cannula implanted in either the amygdala or the internal capsule. Regional inhibition of protein synthesis was determined by analysis of autoradiograms from different brain levels using an image analyzing computer to measure the optical densities of microscopic areas corresponding to discrete neuroanatomical structures. Regional patterns of inhibition were assessed: (a) after injection of different doses of CHX (10 or 20 microgram) into the amygdala; (b) after injection of 20 microgram of CHX into the amygdala or internal capsule; and (c) at different times (0.5, 3, 6 and 24 h) after injection of 20 microgram of CHX into the amygdala. Quantitative results are presented for the temporal and spatial patterns of protein synthesis inhibition caused by CHX injection. Since injection of CHX into the amygdala resulted in a profound inhibition of protein synthesis in both the amygdala and internal capsule while injection into the thermal capsule only caused a marked inhibition in the capsule itself, these results provide a possible explanation for our earlier observation that injection of CHX into the amygdala produced a retention deficit while injection into the adjacent internal capsule had no effect on memory function. These observations on protein synthesis inhibition support our earlier hypothesis that CHX injected into the amygdala might impair memory by virtue of its action on amygdaloid function rather than as a result of its effect on the brain as a whole.

Amygdala↗