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Mitochondria as subcellular targets for clinically useful anthracyclines
1Group Drug Targeting, Max-Delbrueck-Center for Molecular Medicine, Robert Roessle Strasse 10, D-13125 Berlin, Germany.
Abstract:
Due to the widespread use of anthracyclines as antitumor agents, a large number of investigations have been reported analyzing clinical and molecular aspects of these quinone antibiotics. While the high affinity of anthracyclines towards chromosomal DNA has been held responsible for their antitumor activity, an increasing amount of data is being accumulated showing that these drugs also target mitochondria thus interfering with major mitochondrial functions. Since this toxicity of anthracyclines towards mitochondria is associated with side effects significantly limiting their chemotherapeutic dose, the corresponding underlying mechanisms need to be understood. Bioenergetic failure, enzyme inhibitions, lipid peroxidations, induction of membrane disorders as well as the initiation of oxidative stress are being attributed to the accumulation of anthracyclines at or inside mitochondria. In this review the wide spectrum of possible mode of actions of these antibiotics leading to mitochondrial dysfunctions will be presented and discussed.
Insights
Anthracyclines fight tumors by targeting DNA, but also harm mitochondria. Understanding this mitochondrial toxicity is key to improving cancer chemotherapy and reducing side effects.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Anthracyclines are widely used antitumor agents.
- Their DNA-binding is linked to anticancer effects.
- Emerging evidence shows mitochondrial targeting by anthracyclines.
Purpose of the Study:
- To review the mechanisms of anthracycline-induced mitochondrial dysfunction.
- To discuss the link between mitochondrial toxicity and chemotherapy side effects.
Main Methods:
- Literature review of existing studies on anthracyclines and mitochondria.
- Analysis of biochemical and molecular data on drug-target interactions.
- Discussion of reported effects on mitochondrial functions.
Main Results:
- Anthracyclines accumulate in or at mitochondria.
- Mitochondrial dysfunction includes bioenergetic failure, enzyme inhibition, lipid peroxidation, membrane disruption, and oxidative stress.
- This toxicity limits therapeutic doses and causes side effects.
Conclusions:
- Mitochondrial targeting is a significant aspect of anthracycline action.
- Understanding these mechanisms is crucial for developing safer and more effective cancer therapies.