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Published on: November 16, 2016
4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210 leukemia cells
J W Lawrence1, S Darkin-Rattray, F Xie
1Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville 32610-0267.
Abstract:
The 4-quinolone antibiotics nalidixic acid and ciprofloxacin are potent inhibitors of the bacterial type II topoisomerase DNA gyrase. Treatment of mouse L1210 leukemia cells with these drugs resulted in a delayed inhibition of cell proliferation. Prior to inhibition of cell proliferation, there was a time-dependent decrease in the cellular content of mitochondrial DNA (mtDNA). The decrease in mtDNA was associated with a decrease in the rate of mitochondrial respiration and an increase in the concentration of lactate in the growth medium. Inhibition of cell proliferation by 4-quinolones was reversible upon drug washout. However, there was a 2- to 4-day lag before the growth rate returned to normal levels. This was preceded by an increase in mtDNA content and mitochondrial respiration. These studies suggest that inhibition of mammalian cell proliferation by 4-quinolone drugs is related to the selective depletion of mtDNA.
Insights
4-quinolone antibiotics like nalidixic acid and ciprofloxacin inhibit mammalian cell proliferation by selectively depleting mitochondrial DNA (mtDNA). This depletion impairs respiration and is reversible upon drug removal, with a lag period for recovery.
Area of Science:
- Pharmacology
- Molecular Biology
- Cell Biology
Background:
- 4-quinolone antibiotics are known inhibitors of bacterial DNA gyrase.
- Their effects on mammalian cells, particularly at the mitochondrial level, are less understood.
Purpose of the Study:
- To investigate the mechanism by which 4-quinolone antibiotics inhibit mammalian cell proliferation.
- To determine the role of mitochondrial DNA (mtDNA) in this process.
Main Methods:
- Treatment of mouse L1210 leukemia cells with nalidixic acid and ciprofloxacin.
- Monitoring of cell proliferation, mtDNA content, mitochondrial respiration, and lactate production.
- Assessment of drug washout effects on cell recovery.
Main Results:
- 4-quinolones caused a delayed inhibition of cell proliferation.
- A time-dependent decrease in mtDNA content was observed prior to proliferation inhibition.
- Decreased mtDNA correlated with reduced mitochondrial respiration and increased lactate.
- Inhibition was reversible, with a 2-4 day lag for growth rate normalization, preceded by mtDNA and respiration recovery.
Conclusions:
- 4-quinolone-induced inhibition of mammalian cell proliferation is linked to selective depletion of mtDNA.
- Mitochondrial dysfunction plays a key role in the cytotoxic effects of these antibiotics on mammalian cells.
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