Inhibition of Mammalian Mitochondrial Protein Synthesis by Oxazolidinones

McKee, Edward E.; Ferguson, Mary; Bentley, Alice T.; Marks, Thomas A.

doi:10.1128/aac.01411-05

Cited by 233 publications

(194 citation statements)

References 38 publications

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“…Chloramphenicol, a ribosomal antibiotic that binds to the peptidyl transferase center in the bacterial ribosome, 14 is known to impair protein synthesis in isolated rat heart mitochondria. 7 Our results from the HCS assay showed that the macrolides, erythromycin (Fig. 3C), azithromycin, and telithromycin, did not impair Complex IV-subunit 1 levels in THLE-2 cells.…”

Section: Discussionmentioning

confidence: 97%

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High-Content Screening for Compounds That Affect mtDNA-Encoded Protein Levels in Eukaryotic Cells

et al. 2010

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Compounds that interfere with the synthesis of either mitochondrial DNA or mtDNA-encoded proteins reduce the levels of 13 proteins essential for oxidative phosphorylation, leading to a decrease in mitochondrial adenosine triphosphate (ATP) production. Toxicity caused by these compounds is seldom identified in 24-to 72-h cytotoxicity assays due to the low turnover rates of both mtDNA and mtDNA-encoded proteins. To address this problem, the authors developed a 96-well format, high-content screening (HCS) assay that measures, in eukaryotic cells, the level of Complex IV-subunit 1, an mtDNA-encoded protein synthesized on mitochondrial ribosomes, and the level of Complex V-α subunit, a nuclear DNAencoded protein synthesized on cytosolic ribosomes. The effect of several antibiotics and antiretrovirals on these 2 proteins was assessed, in transformed human liver epithelial cells, 6 days after compound treatment. The results confirmed effects of drugs known to reduce mtDNA-encoded protein levels and also revealed novel information showing that several fluoroquinolones and a macrolide, josamycin, impaired expression of mtDNA-encoded proteins. The HCS assay was robust with an average Z′ factor of 0.62. The assay enables large-scale screening of compounds to identify those that potentially affect mtDNA-encoded protein levels and can be implemented within a screening paradigm to minimize compound attrition. (Journal of Biomolecular Screening 2010:937-948)

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Section: Discussionmentioning

confidence: 97%

“…7 Nagiec et al 6 have shown, by Western blotting, that linezolid decreases Complex IV-subunit 1 levels in human erythroleukemia cells. The decrease in Complex IV-subunit 1 seen in linezolid-treated THLE-2 cells in our HCS assay is in accord with these results.…”

Section: Discussionmentioning

confidence: 99%

High-Content Screening for Compounds That Affect mtDNA-Encoded Protein Levels in Eukaryotic Cells

et al. 2010

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“…14,19 Interestingly, the mean half-maximal inhibitory concentration of linezolid against mitochondrial protein synthesis (IC50) in rat and rabbit heart and liver mitochondria was 4.31 mg/L. 20 Accordingly, it may be reasonably supposed that linezolid-induced thrombocytopenia might occur more frequently among patients who have linezolid plasma concentrations above this threshold value for the entire dosing interval. 21 Of the 30 patients 10% patients showed marked decrease in haemoglobin value when compared from baseline to subsequent weeks till 21days, these events may be drug related as the linezolid plasma concentration (Cmin) was found more in those patients too.…”

Section: Discussionmentioning

confidence: 99%

Association between serum linezolid concentration and haematological toxic effects: a longitudinal study

2017

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Background: Linezolid is a commonly used antibiotic and reported various drug related adverse effects mainly haematological toxicity like thrombocytopenia, leukopenia and anaemia. But a significant association between linezolid plasma concentration and drug related adverse effects are not documented yet. This longitudinal observational study aims to study the incidence of drug related haematological toxicities and its association with serum Linezolid concentration and also evaluate the clinical outcome.Methods: After obtaining informed consent, each patient (18-50years) was given linezolid (600mg/12hourly), and evaluated for haematological (haemoglobin, platelets, WBCs), renal (as serum creatinine), and hepatic (as serum transaminases status), together with an assessment of drug C min values. These evaluations were repeated once a week or in concomitance with the development of an adverse event up to the end of linezolid therapy. The parametric dependent ‘t’ test was applied (p<0.05) and normality of data were performed by Kolmogorov Smirnov test, follows normal distribution.Results: There was significant reduction in platelet count and haemoglobin value seen from baseline till end of treatment (p<0.001) and there was 13% reduction in WBC count in all patients on day 14 when compared to baseline (p<0.001) indicating haematological toxicity according to WHO toxicity grading scale. All the patients (n=8; 26.6%) who developed drug related haematological toxicity also showed comparable increase in plasma linezolid concentration (C min) >10mg/L at the end of 14days.Conclusions: The capability to monitor plasma linezolid concentration (C min; trough value) once a week may lead to a significant improvement in clinical use of the drug both in terms of efficacy and tolerability as the study observed that there is association between linezolid concentration and risk of developing drug related haematological toxicity.

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“…As shown in Figure 1, meclocycline and minocycline significantly inhibit cellular proliferation when combined with ATO, compared to either agent alone, in both SK-Mel-19 and M-14 melanoma cells. Because previous studies showed that the antiproliferative effects of tetracyclines in certain mammalian cells results from binding to, and inhibition of, mitochondrial ribosomes (28), we hypothesized that the sensitization to ATO was due to inhibition of mammalian mitochondrial protein synthesis by the tetracyclines (18).…”

Section: Tetracyclines and Thiostrepton Enhance Ato-mediated Growth Imentioning

confidence: 99%

Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism

Bowling

Doudican

Manga

et al. 2008

Cancer Chemother Pharmacol

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Purpose-Current standard chemotherapeutic regimens for malignant melanoma are unsatisfactory. Although in vitro studies of arsenic trioxide (ATO) have demonstrated promise against melanoma, recent phase II clinical trials have failed to show any significant clinical benefit when used as a single agent. To enhance the efficacy of ATO in the treatment of melanoma, we sought to identify compounds that potentiate the cytotoxic effects of ATO in melanoma cells. Through a screen of 2000 marketed drugs and naturally occurring compounds, a variety of antibiotic inhibitors of mitochondrial protein translation were identified.Methods-The mechanism of action for the most effective agent identified, thiostrepton, was examined in a panel of melanoma cells. Effects of combinatorial ATO and thiostrepton treatment on cytotoxicity, apoptosis, mitochondrial protein content, and reactive oxygen species (ROS) were assessed.Results-Thiostrepton (1μM) sensitized 3 out of 5 melanoma cell lines to ATO-mediated growth inhibition. Treatment with thiostrepton resulted in reduced levels of the mitochondrial-encoded protein cytochrome oxidase I (COX1). Exposure to thiostrepton in combination with ATO resulted in increased levels of cleaved poly (ADP-ribose) polymerase and cellular ROS. The growth inhibitory and pro-apototic effects of addition of the ATO/thiostrepton combination were reversed by the free radical scavenger N-acetyl-l-cysteine.Conculsions-Our data suggest that thiostrepton enhances the cytotoxic effects of ATO through a ROS-dependent mechanism. Co-administration of oxidative stress-inducing drugs such as thiostrepton in order to enhance the efficacy of ATO in the treatment of melanoma warrants further investigation.

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Inhibition of Mammalian Mitochondrial Protein Synthesis by Oxazolidinones

Cited by 233 publications

References 38 publications

High-Content Screening for Compounds That Affect mtDNA-Encoded Protein Levels in Eukaryotic Cells

High-Content Screening for Compounds That Affect mtDNA-Encoded Protein Levels in Eukaryotic Cells

Association between serum linezolid concentration and haematological toxic effects: a longitudinal study

Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism

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