Mitochondria as subcellular targets for clinically useful anthracyclines.
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.
Jung
K
K
Group Drug Targeting, Max-Delbrueck-Center for Molecular Medicine, Robert Roessle Strasse 10, D-13125 Berlin, Germany.
Reszka
R
R
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D008563:Membrane Lipids / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D008563:Membrane Lipids; D004317:Doxorubicin; D009247:NADH, NADPH Oxidoreductases