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Modifications of oxido-reductase activities in adriamycin-resistant leukaemia K562 cells
M Denis-Gay1, J M Petit, J P Mazat
1Institut de Biotechnologie, Faculté des Sciences, Limoges, France.
Abstract:
Adriamycin (ADR), a well-known antitumoral drug, interacts with DNA (nuclear and mitochondrial) and cardiolipin. Moreover, ADR induces numerous mitochondrial modifications in sensitive cells. However, no results have yet been obtained as to the repercussions of drug effects on oxido-reductase activities in ADR-resistant cells. To analyze mitochondrial damage induced by ADR treatment, we investigated lactate content, oxygen consumption, respiratory chain activities, and cytochrome content in ADR-sensitive K562 cells and two ADR-resistant variants (K562/R0.2 and K562/R0.5 cells). Biochemical investigations in ADR-resistant cells showed several mitochondrial modifications (in comparison to the parental cell line) according to the variant line and the physiologic state. More particularly, in K562/R0.5 cells cytochrome c (cyt c) oxidase (COX; EC 1.9.3.1) activity and cytochrome aa3 content dramatically decreased since cells enter into the stationary phase. Regardless of the number of multidrug-resistant cell subcultures in ADR-free medium, the cytochrome c oxidase activity in the stationary phase remained unchanged, indicating an irreversible effect of the drug. These alterations could correspond to several modifications of the nuclear and/or mitochondrial genome(s) following acquisition of the ADR resistance phenotype by K562 cells.
Insights
Adriamycin (ADR) resistance in K562 cells causes irreversible mitochondrial damage, specifically decreasing cytochrome c oxidase activity. This suggests genetic modifications in resistant cells.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Adriamycin (ADR) is an antitumoral drug that interacts with DNA and cardiolipin, inducing mitochondrial modifications in sensitive cells.
- The effects of ADR on oxido-reductase activities in ADR-resistant cells remain largely uncharacterized.
Purpose of the Study:
- To investigate mitochondrial damage induced by ADR treatment in sensitive and resistant K562 cells.
- To analyze the repercussions of ADR on oxido-reductase activities, lactate content, oxygen consumption, and cytochrome content.
Main Methods:
- Biochemical investigations were performed on ADR-sensitive K562 cells and two ADR-resistant variants (K562/R0.2 and K562/R0.5).
- Measurements included lactate content, oxygen consumption, respiratory chain activities, and cytochrome content.
Main Results:
- ADR-resistant cells exhibited mitochondrial modifications compared to the parental cell line.
- In K562/R0.5 cells, cytochrome c oxidase activity and cytochrome aa3 content significantly decreased upon entering the stationary phase.
- This decrease in cytochrome c oxidase activity was irreversible, even after culturing in ADR-free medium.
Conclusions:
- ADR-induced mitochondrial damage, particularly to cytochrome c oxidase, is an irreversible consequence of acquiring ADR resistance.
- These alterations may stem from modifications in the nuclear and/or mitochondrial genomes associated with the ADR resistance phenotype.