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PubMed1993

Suppressive effect of cycloheximide on behavioral sensitization to methamphetamine in mice.

The effect of a protein synthesis inhibitor, cycloheximide, on behavioral sensitization to methamphetamine was investigated in mice. As indicated by the sensitization tests, repeated injection of methamphetamine (2 mg/kg i.p.) at intervals of 3 and 4 days resulted in a progressive augmentation of the locomotor-stimulating effect of methamphetamine. This phenomenon, called locomotor sensitization, was attenuated by simultaneous treatment with cycloheximide (120 mg/kg i.p.) at the time of stimulant injection. In contrast, when mice were treated with cycloheximide 4 h after stimulant injection, locomotor activity was progressively augmented in the same way as observed in mice receiving repeated injections of methamphetamine alone. On challenge, it was noted that locomotor activity was significantly higher in mice injected repeatedly with the stimulant alone and in those mice treated with the inhibitor 4 h after the stimulant injection compared to the saline-treated control mice. However, mice that had been simultaneously treated with cycloheximide and methamphetamine showed almost the same locomotor activity as the saline-treated control mice. These observations indicated that the locomotor sensitization to methamphetamine was possibly suppressed by simultaneous treatment with cycloheximide. We then examined the dose- and time-dependent nature of the effect of cycloheximide on locomotor sensitization. The stimulation of locomotion observed after repeated injection of the stimulant at a dose of 1.5 mg/kg was significantly attenuated by simultaneous treatment with 120 or 240 mg/kg of cycloheximide, but not by treatment with 60 mg/kg of the inhibitor. However, all the treatments failed to suppress the development of locomotor sensitization elicited by 3 mg/kg of methamphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Cycloheximide: an adrenergic agent.

Cycloheximide, a widely used inhibitor of protein synthesis, stimulates glycogenolysis, gluconeogenesis and ureogenesis in isolated rat hepatocytes. The effects of cycloheximide were compared to those of norepinephrine. Both agents, cycloheximide and norepinephrine, produced slight increases in the levels of cyclic AMP (30% increases) which were blocked by propranolol. Interestingly, it was found that the metabolic actions of norepinephrine and cycloheximide (stimulation of glycogenolysis, gluconeogenesis and ureogenesis) were only slightly diminished by the beta adrenergic antagonist propranolol but abolished by the selective alpha 1 adrenergic antagonist prazosin. The ability of cycloheximide to inhibit protein synthesis was not affected by either prazosin or propranolol. It is concluded that the stimulation of glycogenolysis, gluconeogenesis and ureogenesis by cycloheximide in rat hepatocytes, is an effect of the antibiotic independent of its ability to inhibit protein synthesis and that is mediated through activation of alpha 1 adrenoceptors. The adrenergic activity of cycloheximide should be considered when this drug is used as an inhibitor of protein synthesis.

Animals↗
PubMed1977

Cycloheximide produces adult-like retention deficits of prior learning in infant mice.

Utilizing a dosage of cycloheximide which was found to inhibit cerebral protein synthesis by almost 90% after injection, separate groups of 13-day-old mice received either cycloheximide or saline followed by 0 (control), 15, or 25 training trials in a discriminated shock-escape T-maze. Twenty-four hr later, each mouse was treated with cycloheximide or saline and tested for retention by an additional 25 trails in the T-maze. As reflected by correct choice-point turns, the results suggest that whereas salinetreated mice demonstrated reliable retention of prior learning, cycloheximide treated mice exhibited memory impairment; cycloheximide per se had no effect on performance during either original training or retest. A final experiment indicated that this memory impairment was not due to cycloheximide's general debilitating side effects at the time of retention testing. Taken together, these data suggest that protein synthesis inhibition during training impaired consolidation and/or retrieval processes involved in memory. The biochemical and behavioral effects following cycloheximide injection in 13-14-day-old mice in the present study parallel those reported with adult animals and lend indirect support to the hypothesis that the 24-hr memory capacity exhibited by these young mice reflects the early functioning of those processes involved in adult long-term memory.

Amnesia↗
PubMed1991

Mechanisms involved in the stimulation by cycloheximide of prostaglandin production in the guinea-pig uterus.

Cycloheximide produced a large increase in prostaglandin (PG) E2 output and smaller increases in PGF2 alpha and 6-keto-PGF1 alpha when superfused over the guinea-pig uterus for 20 min. This stimulation of the outputs of these 3 PGs by cycloheximide did not require extracellular calcium. TMB-8 (an intracellular calcium antagonist) had no effect on the stimulation of PGE2 output by cycloheximide, but it completely prevented the stimulation of PGF2 alpha and 6-keto-PGF1 alpha outputs. W-7 (a calmodulin antagonist) had no effect on the stimulation of PGE2 and PGF2 alpha outputs by cycloheximide, but it partially reduced and delayed the stimulation of 6-keto-PGF1 alpha output. Neomycin (a phospholipase C inhibitor) did not prevent the increases in PGE2 and 6-keto-PGF1 alpha outputs produced by cycloheximide. However, neomycin (5 and 10 mM, but not 1 mM) inhibited the small increases in PGF2 alpha caused by cycloheximide. On its own, neomycin produced a dose-dependent, transient increase in 6-keto-PGF1 alpha output without affecting the outputs of PGF2 alpha and PGE2. It is concluded that different mechanisms are involved in the processes by which cycloheximide stimulates the syntheses of PGE2, PGF2 alpha and 6-keto-PGF1 alpha in the guinea-pig uterus.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Regulation of tyrosine aminotransferase messenger ribonucleic acid in rat liver. effect of cycloheximide on messenger ribonucleic acid turnover.

Tyrosine aminotransferase messenger ribonucleic acid (mRNA) activity in rat liver was rapidly increased 3-6-fold following in vivo administration of hydrocortisone acetate, dibutyryladenosine cyclic 3',5'-phosphate, or the protein synthesis inhibitor cycloheximide. Treatment with the steroid hormone or cyclic nucleotide in combination with cycloheximide resulted in levels of tyrosine aminotransferase mRNA 10-20-fold greater than control values. These changes in mRNA activity were not accompanied by changes in albumin mRNA or total liver template activity. The rapid decline in tyrosine aminotransferase mRNA activity following cordycepin inhibition of de novo RNA synthesis was prevented by cycloheximide treatment. This protection was not observed when pactamycin was substituted for cycloheximide, demonstrating that the inhibition of protein synthesis per se was not responsible for the stabilization of tyrosine aminotransferase mRNA. Based upon the effects of cycloheximide and pactamycin on rat liver polysome structure, it is concluded that the cycloheximide-mediated increase in tyrosine aminotransferase mRNA activity is the result of stabilization of the mRNA molecule which renders the message less susceptible to inactivation and degradation in the cytoplasm. The action of cycloheximide is very specific for tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, and probably several other mRNAs that code for minor liver proteins that turn over rapidly in response to hormonal or metabolic stimuli.

Animals↗
PubMed1979

Inhibition by cycloheximide of degradation of cytochrome P-450 in primary cultures of adult rat liver parenchymal cells and in vivo.

Degradation of cytochrome P-450 was studied in adult rat liver parenchymal cells in primary monolayer culture. In cells incubated in standard culture medium, the amount of cytochrome P-450 decreased at an accelerated rate relative to either the rate of degradation of total protein in the cells or the turnover of cytochrome P-450 in vivo. This change was succeeded by a spontaneous increase in the activity of haem oxygenase, an enzyme system that converts haem into bilirubin in vitro, measured in extracts from the cultured cells. This finding suggests that the rate of cytochrome P-450 breakdown may be controlled by factor(s) other than the activity of haem oxygenase. The decline in cytochrome P-450 and the subsequent increase in haem oxygenase activity was prevented by incubation of hepatocytes in medium containing an inhibitor of protein synthesis such as cycloheximide, puromycin, actinomycin D, or azaserine. The effect of cycloheximide appeared to be due to decreased breakdown of microsomal (14)C-labelled haem. By contrast, cycloheximide was without effect on the degradation of total protein, measured either in homogenates or in microsomal fractions prepared from the cultured cells. These results suggest that the conditions of cell culture stimulate selective degradation of cytochrome P-450 by a process that is inhibited by cycloheximide and hence may require protein synthesis. The findings in culture were verified in parallel studies of cytochrome P-450 degradation in vivo. After administration of bromobenzene, the degradation of the haem moiety of cytochrome P-450 was accelerated in vivo in a manner resembling that observed in cultured hepatocytes. Administration of cycloheximide to either bromobenzene-treated rats or to untreated rats decreased the degradation of the haem moiety of cytochrome P-450. However, the drug failed to affect degradation of haem not associated with cytochrome P-450, suggesting that cycloheximide is not a general inhibitor of haem oxidation in the liver. These findings confirm that the catabolism of hepatic cytochrome P-450 haem is controlled by similar cycloheximide-sensitive processes in the basal steady state in vivo, as stimulated by bromobenzene in vivo, or in hepatocytes under the conditions of cell culture. We conclude that the rate-limiting step in this process appears to require protein synthesis and precedes cleavage of the haem ring.

Animals↗
PubMed1982

Control of cell protein catabolism in rat liver. Effects of starvation and administration of cycloheximide.

1. The loss of liver protein occurring in rats starved for 24 h was largely prevented by the administration of repeated doses of cycloheximide, an inhibitor of protein synthesis. Similar effects were produced on tubulin, a 'fixed' liver protein. 2. Starvation accelerated, whereas cycloheximide markedly lowered, the rate of protein radioactivity decay after labelling with [3H]valine or [14C]bicarbonate, indicating that changes in catabolic rates played an important role in the above regulations of liver protein mass. 3. The total activity of several lysosomal hydrolases showed little change in livers of starved rats, but a marked progressive decline developed after the administration of cycloheximide, particularly in the activities of cathepsins B, D and L as well as acid ribonuclease. There was no evidence that these changes might be due to endogenous inhibitors (at least for cathepsin B activity, which fell to less than 30% of the control values) or enzyme leakage into the bloodstream; rather, plasma beta-galactosidase and beta-N-acetylglucosaminidase activities fell progressively during the cycloheximide treatment. 4. Endogenous proteolytic rates, measured in vitro by incubating subcellular preparations from livers prelabelled in vivo with [3H]valine, were markedly decreased in cycloheximide-treated animals. 5. The osmotic fragility of hepatic lysosomes, appreciably enhanced in starved animals, after cycloheximide treatment was found to be even lower than in fed controls. 6. The present data are consistent with the view that in starved animals the loss of liver protein is mostly accounted for by increased breakdown, due, in part at least, to enhanced autophagocytosis. 7. Cycloheximide largely counteracted these effects of starvation, altering the liver from being 'poised' in a proteolytic direction to a protein-sparing condition. The present data suggest that, besides suppression of the autophagic processes, a decrease in the lysosomal proteolytic enzyme system may also play a role in this regulation, and they seem to provide further circumstantial evidence for the existence of co-ordinating mechanisms between protein synthesis and degradation.

Animals↗
PubMed2000

Superinduction of CYP1A1 gene expression. Regulation of 2,3,7, 8-tetrachlorodibenzo-p-dioxin-induced degradation of Ah receptor by cycloheximide.

Cycloheximide superinduces the transcription of CYP1A1 in the presence of an agonist for the Ah receptor (AhR). To investigate the molecular target for "superinduction," we analyzed the agonist-induced degradation of AhR. Whereas 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR, induces a rapid reduction of the AhR protein, cycloheximide blocks the down-regulation of steady state AhR. Analyses of the turnover of AhR reveal that cycloheximide blocks the shortening of the half-life of AhR by TCDD. Blocking of the TCDD-induced AhR degradation requires inhibition of protein synthesis, because (a) cycloheximide inhibits protein synthesis at the concentration at which it causes superinduction and inhibition of AhR degradation; and (b) puromycin, an inhibitor of protein synthesis by mimicking aminoacyl-tRNA, also blocks the TCDD-induced AhR degradation. The blocking of the TCDD-induced AhR degradation correlates with the superinduction of CYP1A1 gene expression in a time- and dose-dependent manner. Furthermore, cycloheximide is shown to increase the accumulation of the TCDD-activated AhR and the functional AhR x Arnt complex in nucleus. Collectively, our results reveal a mechanism of superinduction by cycloheximide by enhancing the stability of agonist-activated AhR. The finding that inhibition of protein synthesis blocks the TCDD-induced AhR turnover implicates a cycloheximide-sensitive, labile factor (designated as AhR degradation promoting factor, or ADPF) in controlling the removal of agonist-activated AhR in nucleus.

Animals↗
PubMed2006

Selective clearance of macrophages in atherosclerotic plaques by the protein synthesis inhibitor cycloheximide.

Macrophages are an essential component of unstable atherosclerotic plaques and play a pivotal role in the destabilization process. We have demonstrated previously that local delivery of the mammalian target of rapamycin (mTOR) inhibitor everolimus selectively clears macrophages in rabbit plaques. Because mTOR controls mRNA translation, inhibition of protein synthesis might induce selective macrophage cell death. We therefore investigated in the present study the effect of the protein synthesis inhibitor cycloheximide on macrophage and smooth muscle cell (SMC) viability. In vitro studies with cultured macrophages and SMCs showed that cycloheximide induced selective apoptosis of macrophages in a concentration- and time-dependent manner. Moreover, macrophages could be selectively depleted in rabbit carotid artery rings with collar-induced atherosclerotic plaques after in vitro treatment with cycloheximide. Local in vivo administration of cycloheximide via osmotic minipumps to rabbit carotid arteries with collar-induced atherosclerotic plaques significantly reduced the macrophage but not the SMC content. Cycloheximide-treated plaques showed signs of apoptosis (increased terminal deoxynucleotidyl transferase end labeling and fluorescein isothiocyanate-Val-Ala-dl-Asp(O-methyl)-fluoromethylketone labeling) that did not colocalize with SMCs. Organ chamber studies demonstrated that the functionality of SMCs and the endothelium were not influenced by cycloheximide treatment. All together, these findings demonstrate that cycloheximide decreases the macrophage load in atherosclerotic plaques by induction of apoptosis without changing SMC content or contractility.

Animals↗
PubMed1988

Cycloheximide efflux in antibiotic-adapted cells of the fungus Mucor racemosus.

Mucor racemosus cells adapted to either cycloheximide or trichodermin were approximately 40-fold more resistant to cycloheximide than nonadapted cells. Ribosomes isolated from adapted and nonadapted cells were equally sensitive to cycloheximide in an in vitro poly(U) translation assay. There was no detectable modification of cycloheximide by adapted cells. Uptake of drug by nonadapted and adapted cells was characterized by a rapid initial accumulation during the first 2 min of incubation with [3H]cycloheximide, followed by a steady-state intracellular drug concentration well below that of the medium. The steady-state drug concentration was approximately 10-fold lower in adapted cells than in nonadapted cells. Treatment of cells with sodium azide or dinitrophenol abolished the difference between uptake of drug by nonadapted and adapted cells and resulted in intracellular drug levels equal to that of the medium. Direct efflux measurements showed that adapted cells loaded with cycloheximide were able to excrete the drug far more rapidly than nonadapted cells. These results suggest that both nonadapted and adapted cells possess an energy-dependent efflux mechanism for transporting cycloheximide and that resistance in adapted cells is due to increased efficiency of transport.

Amino Acids↗
PubMed1974

Effect of cycloheximide on RNA metabolism early in productive infection with adenovirus 2.

The presence of cycloheximide during the early phase of adenovirus 2 replication causes an increase in the virus-specific content of newly synthesized mRNA. The total cytoplasmic RNA from control cultures labeled 2 to 5 h after infection hybridized to viral DNA 0.8%, whereas RNA synthesized in the presence of cycloheximide annealed 6%. Cytosine arabinoside, an inhibitor of DNA synthesis, did not affect the percent hybridization to viral DNA. Oligo(dT)-cellulose chromatography was used to purify the portion of cytoplasmic RNA containing poly(A). The poly(A)-containing RNA from cultures labeled in the presence of cycloheximide hybridized to viral DNA 32% as compared to 2.2% for RNA from control cultures. Hybridization-inhibition experiments between RNAs from control- and cycloheximide-treated cultures demonstrated that the cultures treated with cycloheximide did not have an increased content of viral RNA or a new class of viral RNA sequences. Therefore, the increased hybridization appears to be caused by a reduction in synthesis of cellular cytoplasmic mRNA. Nucleoplasmic RNAs lacking and containing poly(A) were annealed to viral DNA. For both classes, RNA from cultures treated with cycloheximide hybridized 5- to 10-fold more than RNA from control-infected cultures. Therefore, the increased hybridization of cytoplasmic RNA synthesized in the presence of cycloheximide is caused either by reduced transcription of the cellular genome or by greatly increased instability of cellular heterogeneous nuclear RNA.

Adenoviridae↗
PubMed2006

On the effects of cycloheximide on cell motility and polarisation in Dictyostelium discoideum.

BACKGROUND: Cycloheximide is a protein synthesis inhibitor that acts specifically on the 60S subunit of eukaryotic ribosomes. It has previously been shown that a short incubation of Dictyostelium discoideum amoebae in cycloheximide eliminates fluid phase endocytosis. RESULTS: We found that treatment with cycloheximide also causes the amoebae to retract their pseudopodia, round up and cease movement. Furthermore, fluid phase endocytosis, phagocytosis and capping cease in the presence of 2 mM cycloheximide, although membrane uptake, as measured using FM1-43, is unaffected. In the presence of cycloheximide, aggregation-competent amoebae sensitive to cAMP, although round, can still localise CRAC, ABP120, PI3K and actin polymerisation in response to a micropipette filled with cAMP. The behaviour of wild-type amoebae in the presence of cycloheximide is surprisingly similar to that of amoebae having a temperature-sensitive version of NSF at the restrictive temperature. CONCLUSION: Our results may suggest that, upon cycloheximide treatment, either a labile protein required for polarised membrane recycling is lost, or a control mechanism linking protein synthesis to membrane recycling is activated.

Actins↗
PubMed1989

The enhancing effect of adrenocorticotropin on adrenal 3-hydroxy-3-methylglutaryl coenzyme A reductase messenger ribonucleic acid level is inhibited by aminoglutethimide but not by cycloheximide.

3-Hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase activity and reductase mRNA level were determined in adrenals from hamsters treated with ACTH, with or without cycloheximide or aminoglutethimide. Both reductase activity and reductase mRNA level were similarly enhanced by ACTH administration compared to levels in NaCl-treated animals. The administration of cycloheximide with ACTH resulted in a 73% decrease in reductase activity compared to control values, but did not prevent the enhancing effect of ACTH on the reductase mRNA level. Furthermore, the administration of cycloheximide alone diminished HMG-CoA reductase activity, but enhanced by 1.1- to 1.6-fold the reductase mRNA level. Coadministration of aminoglutethimide with ACTH also resulted in a decrease (65%) in reductase activity compared to that in NaCl-treated animals. However, coadministration of aminoglutethimide, in contrast to cycloheximide, with ACTH not only prevented the reductase mRNA level increase produced by ACTH, but also resulted in a 30% decrease in the reductase mRNA level compared to that in controls injected with 0.15 M NaCl. In addition, aminoglutethimide alone resulted in 50% and 54% decreases in reductase mRNA level and reductase activity, respectively. Thus, we have shown that both cycloheximide and aminoglutethimide can prevent the enhancing effect of ACTH on HMG-CoA reductase activity, but their modes of action differ. It is likely that the aminoglutethimide inhibition could be the result of a diminution of specific reductase gene transcription, whereas cycloheximide would result in inhibition of the synthesis of specific proteins, including HMG-CoA reductase. In this respect, since the adrenal free cholesterol content was increased in groups treated with ACTH-aminoglutethimide, we postulate that free cholesterol could be one of the important components involved in the regulation of HMG-CoA reductase gene transcription. As for the ACTH-cycloheximide-treated groups, the adrenal free cholesterol content was also increased, but the effect of ACTH on the reductase mRNA level was not prevented, presumably because this drug blocked the synthesis of a putative sterol regulatory protein that is required to repress HMG-CoA reductase gene transcription.

Adrenal Glands↗
PubMed2006

Therapeutic window for cycloheximide treatment after hypoxic-ischemic brain injury in neonatal rats.

We have previously shown that cycloheximide significantly inhibited apoptosis, and reduced ensuing cerebral infarction in a newborn rat model of cerebral hypoxiaischemia. This study was performed to determine the therapeutic window for cycloheximide therapy. Seven day-old newborn rat pups were subjected to 100 min of 8% oxygen following a unilateral carotid artery ligation, and cycloheximide was given at 0, 6, 12 and 24 hr after hypoxia-ischemia (HI). Apoptosis or necrosis was identified by performing flow cytometry with a combination of fluorescinated annexin V and propidium iodide, and the extent of cerebral infarction was evaluated with triphenyl tetrazolium chloride (TTC) at 48 hr and 72 hr after HI, respectively. With cycloheximide treatment at 0 hr after HI, both apoptotic and necrotic cells by flow cytometry were significantly reduced, only necrotic cells were significantly reduced at 6 and 12 hr, and no protective effect was seen if administration was delayed until 24 hr after HI compared to the HI control group. Infarct volume, measured by TTC, was significantly reduced by 92% and 61% when cycloheximide was given at 0 or 6 hr after HI respectively; however, there was an insignificant trend in infarct reduction if cycloheximide was administered 12 hr after HI, and no protective effect was observed when administration was delayed until 24 hr after HI. In summary, cycloheximide was neuroprotective when given within 6 hr after HI in the developing newborn rat brain.

Animals↗
PubMed2001

Activation of cumulus-free equine oocytes: effect of maturation medium, calcium ionophore concentration and duration of cycloheximide exposure.

Two different culture media (TCM-199 and follicular fluid), two activation treatments (10 and 50 micromol calcium ionophore l(-1)) and three culture periods with cycloheximide were evaluated to find effective culture conditions for activation of cumulus-free equine oocytes. Oocytes were collected by scraping the follicle walls of ovaries obtained from an abattoir. Oocytes with expanded cumuli were matured at 38.2 degrees C in a humidified atmosphere of 5% CO(2) in air, in either TCM-199 with 10% fetal bovine serum (FBS) and 5 microU FSH ml(-1), or in 100% follicular fluid derived from a preovulatory follicle 24 h after injection of hCG. After 40--42 h of in vitro maturation, oocytes were denuded by gentle pipetting in TCM-199 plus 10% FBS with hyaluronidase. Oocytes with intact cytoplasmic membranes (n = 398; 94% presumed metaphase II) were treated in protein-free PBS with 10 or 50 micromol calcium ionophore l(-1) for 5 min. After washing, the oocytes were cultured in TCM-199 containing 10% FBS and 10 microg cycloheximide ml(-1) for 6 h, in cycloheximide for 6 h and then in cycloheximide-free medium for 18 h, or in cycloheximide for 24 h. The oocytes were fixed and evaluated by fluorescence microscopy. Oocytes with pronucleus I--II (dense to decondensing chromatin), pronucleus III--IV (decondensed chromatin) or progressing towards the first cleavage division were considered activated. The activation rate for oocytes matured in TCM-199 was significantly (P < 0.05) higher than for oocytes matured in follicular fluid (49% (99/204) versus 35% (60/171), respectively; P < 0.05). Culture with cycloheximide for 24 h resulted in a significantly higher rate of activation (67%, 74/111) than did the 6 h (33%, 44/136) or 6 h plus 18 h (32%, 41/128) treatments. The highest rate of activation (82%) was observed in oocytes matured in TCM-199, treated with 50 micromol calcium ionophore l(-1) and cultured with cycloheximide for 24 h.

Animals↗
PubMedDate not supplied

[Activation of transcription of the tyrosine aminotransferase gene in the rat McA-RN 7777 hepatoma cell line by cycloheximide].

The expression of the tyrosine aminotransferase (TAT) mRNA after cycloheximide treatment was analysed by Northern blotting method in Morris rat hepatoma cell lines. The level of TAT mRNA increased after 6-8 h of cycloheximide treatment only in the McA-RH 7777 cell line. McA-RH 7777 nuclear run-off assay showed that TAT transcription was induced by cycloheximide treatment. Both glucocorticoid and cycloheximide modulated TAT gene transcription in a synergistic way. There was no induction of TAT expression following cycloheximide or cycloheximide glucocorticoid simultaneous treatment in another cell line (McA-RH 8994), while c-myc and c-fos expression was superinduced by cycloheximide treatment. The possible mechanism of transcription regulation and its damage in hepatoma cells is discussed.

Animals↗
PubMed1985

Differential protection of normal and malignant human myeloid progenitors (CFU-GM) from Ara-C toxicity using cycloheximide.

Cycloheximide, a reversible protein synthesis inhibitor, is thought to block DNA replication in normal cells by preventing synthesis of a labile protein. In animal systems, cycloheximide protects normal cells from cytotoxic S-phase specific agents, such as cytosine arabinoside (Ara-C). Malignant cells appear not to be susceptible to cycloheximide-induced cycle arrest and, subsequently, may not be protected from Ara-C cytotoxicity. The effect of cycloheximide on granulocyte/macrophage progenitors (CFU-GM) after in vitro Ara-C exposure was examined using normal human bone marrow, malignant progenitors from patients with chronic myelogenous leukemia (CML), and clonogenic cells from the human acute nonlymphocytic leukemia cell lines HL-60 and KG-1. Mononuclear or clonogenic cells were incubated for one hour with cycloheximide, followed by the addition, for three or 17 hours, of Ara-C before being plated in a methylcellulose culture system. CFU-GM survival was significantly increase if normal cells were treated with cycloheximide before Ara-C exposure. Similar cycloheximide pretreatment of CML progenitors and clonogenic HL-60 and KG-1 cells failed to protect CFU-GM from Ara-C-induced cytotoxicity.

AraC Transcription Factor↗
PubMed1985

The effects of cycloheximide and chloroquine on insulin receptor metabolism. Differential effects on receptor recycling and inactivation and insulin degradation.

The effects of protein synthesis inhibitors and the lysosomotropic agent chloroquine on the metabolism of the insulin receptor were examined. Through the use of the heavy-isotope density shift technique, cycloheximide was found to inhibit both the synthesis of new insulin receptor and the inactivation of old cellular insulin receptor. Upon investigation of the locus of this effect of protein synthesis inhibition, it was found that cycloheximide did not inhibit 1) the translocation of receptor from the cell surface to an intracellular site, 2) the recycling of receptor from the internal site back to the plasma membrane, nor 3) the degradation of insulin. Cycloheximide did, however, rapidly and completely inhibit the inactivation of the insulin receptor. In the presence of extracellular insulin, this effect of cycloheximide resulted in the long-term (6 h) accumulation of receptor in a trypsin-resistant intracellular compartment. Puromycin and pactamycin, protein synthesis inhibitors with mechanisms of action which differ from cycloheximide, produced the same effects on insulin receptor metabolism as cycloheximide, indicating that this effect on receptor metabolism is due to the inhibition of protein synthesis and not a secondary effect of cycloheximide. Actinomycin D also inhibited the inactivation of receptor. Chloroquine inhibited the receptor-mediated degradation of insulin, but had no effect on either the internalization or inactivation of the insulin receptor. The insulin-induced recycling of the internalized receptor was inhibited by chloroquine, possibly through the inhibition of the discharge of insulin from the insulin-receptor complex. From these observations, we suggest that 1) a protein factor is required to inactivate the insulin receptor, 2) this protein and the messenger RNA coding for the protein have short cellular half-lives, and 3) insulin degradation and insulin receptor inactivation are distinct, separable processes which not only occur at different rates, but possibly occur in distinct subcellular locations.

Animals↗