The main drawback of anthracyclines is their ability to cause chronic cardio-myopathy, which is related to damages associated to ROS generation and consequent apoptosis induction. These damages are specially important in cardiac tissue because of the low levels of catalase and the easy inhibition of cardiac selenium-dependent glutathion peroxidase by the anthracyclines, both being key enzymes in the detoxification of hydrogen peroxide.17 Apoptosis induction in cardiac tissue proceeds through activation of NF-kB.2 This is opposite to what is observed in cancer cells in which NF-kB activation usually inhibits apoptosis induced by anthracyclines, a difference that is still not well understood.

The production of radical species by quinone-containing antibiotics was first demonstrated in 1975, and 2 years later DOX and DNR were shown to generate free radicals through redox cycling.18 Because of their ability to bind to nucleic acids, these drugs can be considered as site-specific free radical generators.

From a chemical point of view, the generation of radicals from quinones is based on the captodative effect. While cations are stabilized by electron-releasing groups and anions by electron-withdrawing groups, radicals are best stabilized by the simultaneous presence of both types of substituents (captodative effect). In the case of quinones, the ease of formation of the so-called semiquinone radicals by one-electron reduction is due to their stabilization through the captodative effect of the electron-releasing negatively charged oxygen atom and the electron-withdrawing carbonyl groups (Fig. 4.13).

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