Disease relevance of cycloheximide

• Interestingly, cellular FLICE inhibitory protein (cFLIP) levels, high in PK and low in TK and several other squamous cell carcinoma cell lines, decreased rapidly after treatment of PK with CHX, correlating with the increase in TRAIL sensitivity and caspase-8 processing [1].
• In vivo treatment of mice with ActD/TNF caused hepatic failure, which was significantly reduced by co-treatment with CHX [2].
• Cycloheximide (CHX), an inhibitor of protein synthesis, markedly increased expression of TNF-alpha mRNA in IL-1 beta stimulated CH235-MG cells, indicating that de novo protein synthesis is not required for astroglioma TNF-alpha gene expression [3].

High impact information on cycloheximide

• However, in C/EBPalpha growth-arrested cells, the level of the p21/SDI-1 did not change for > 80 min after CHX addition [4].
• These findings indicated that CHX prevented the degradation of TNF mRNA by inhibiting the synthesis of a labile protein [5].
• Since CHX and A23187 mediated induction of TCR mRNA is both rapid and reversible, it is unlikely that new DNA rearrangements are responsible for the induction [6].
• Under these conditions, Cx selectively prevented the degradation of CK mRNA in a reversible manner [7].
• The calcium ionophore A23187 induces the accumulation of TCR-alpha but not -beta transcripts; and in contrast to CHX, it increases the rate of TCR-alpha gene transcription and the expression of large nuclear TCR-alpha precursor transcripts [6].

Biological context of cycloheximide

• CHX also induces full length TCR-beta transcripts greater than 90-fold while TCR-beta gene transcription increases only 2- to 4-fold [6].
• The dissolution of microfilaments spread peripherally over time and preceded other TNF/CHI-induced effects such as cytoplasmic "boiling," decrease in cell volume, and lysis of the plasma membrane [8].
• Finally, CHX, BIM, and SN50 facilitated the cleavage and activation of procaspase-8 in TRAIL-resistant cells, confirming that inhibition of TRAIL-induced apoptosis occurs at this level and that these agents sensitize MM cells by relieving this block [9].
• In the culture system, hepatocellular DNA fragmentation in the presence of ActD/TNF was observed several hours before lactate dehydrogenase release and was inhibited by CHX [2].
• Apoptosis induced by TNFalpha and CHX was facilitated by FLIP(S) antisense expression but attenuated by sense transfection [10].

Anatomical context of cycloheximide

• Conditions were established for a time-window during which cycloheximide (Cx) produced a virtually total arrest of protein synthesis in myotubes that was reversible upon removal of the inhibitor [7].
• In this report, we examine the mechanism of cytolysis in a 3T3-like mouse cell line, C3HA, which was sensitized to TNF by treatment with CHI [8].
• The disruption of microfilaments, which was observed within 15 min of treatment, was not seen in untreated cells or in cells treated with either TNF or CHI alone [8].
• We found that an early change in TNF/CHI-treated cells was a significant loss of stress fibers in perinuclear areas of the cytoplasm [8].
• Cytochalasin E, which disrupts microfilaments, induced cytolysis of TNF-treated cells even in the absence of CHI; however, demecolcine, which depolymerizes microtubules, did not sensitize cells to TNF [8].

Associations of cycloheximide with other chemical compounds

• Blocking protein synthesis promoted folding and export of ER-retained GFP-PDS, as demonstrated by surface-biotinylation analysis and by CHX- or puromycin-induced accumulation of YFP-PDS in the Golgi apparatus during a 20 degrees C temperature-block experiment [11].
• The regulation of LPS-stimulated TNF alpha mRNA expression in vitro was also investigated by employing the protein synthesis inhibitor cycloheximide (CHX) [12].
• Exposure of human fibroblasts to inhibitors of protein synthesis with different mechanisms of action (e.g., puromycin, pactamycin, or CHX) all generated hexose transport increases in a concentration-dependent fashion correlating with their increasing inhibitory effects on protein synthesis [13].
• These apoptotic phenomena induced by 2CdA were inhibited by cycloheximide (CHX; a protein synthesis inhibitor), deoxycytidine (dC; a substrate of deoxycytidine kinase), acetyl Ile-Glu-Thr-Asp aldehyde (Ac-IETD-CHO; a caspase-8 inhibitor) and acetyl Asp-Glu-Val-Asp aldehyde (Ac-DEVD-CHO; a caspase-3 inhibitor) [14].
• Further, dominant negative IkappaB attenuated the CHX and DENSPM-induced SSAT expression and mitochondria damage [15].

Gene context of cycloheximide

• CHX increased the stability of both IL-1 alpha and IL-1 beta mRNA, demonstrating the existence of a post-transcriptional form of control [16].
• In the absence of CHX, 259 and 125 genes were up or down-regulated respectively; only 38 and 24 of these genes were up and down-regulated by p53 also in the presence of CHX and are considered primary targets in this cell line [17].
• The CHM-superinduced COX-2 mRNA was subject to a rapid degradation after removal of CHM (T1/2 < 1 hr) [18].
• Irrespective of STAT1 status, TNF induced cytotoxic effects in the presence of cycloheximide (CHX) in both cell types [19].
• In serum-free medium containing interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF), the early induction of IFN-alpha mRNA became resistant to CHX, and, in contrast to FBS and CM supplemented medium, this was observed also without a preincubation of the PBMCs [20].

Analytical, diagnostic and therapeutic context of cycloheximide

• Chromatin immunoprecipitation (ChIP) assay showed that NFkappaB was indeed bound to the SSAT promoter after CHX treatment [15].
• ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion [21].

References