Molecular Mechanisms of the Cardiotoxic Action of Anthracycline Antibiotics and Statin-Induced Cytoprotective Reactions of Cardiomyocytes

Cardiotoxicity, a well-recognized side effect of anthracycline antibiotics limits their use in the treatment of malignant processes in some patients. The review considers the main causes of the cardiomyocyte susceptibility to the damaging effect of anthracyclines, primarily associated with increased free radical processes. Currently, research is widely carried out to find ways to reduce anthracycline cardiotoxicity, in particular, the use of cardioprotective agents in the complex treatment of tumors. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve the function and metabolism of the cardiovascular system under various pathological conditions, therefore, it is proposed to use statins to reduce cardiotoxic complications of chemotherapy. Statins exhibit direct (hypolipidemic) and pleiotropic effects determined by inhibition of mevalonic acid synthesis and downstream biochemical cascades mediating their cardioprotective properties. The main point of intersection of the pharmacological activity of anthracyclines and statins is their ability to regulate the functioning of small GTPases of the Rho family: anthracyclines and statins cause opposite effects on the Rho proteins. The effect of statins on the modification and membrane dislocation of Rho proteins mediates their indirect antioxidant, anti-inflammatory, endothelioprotective, and antiapoptotic effects. Special attention in the review is paid to the mechanism of statin inhibition of the doxorubicin blockade of the DNA-topoisomerase complex, which may be important for prevention of the cardiotoxic damage during chemotherapy. At the same time, it should be noted that the use of statins can be accompanied by adverse side effects: provocation of increased insulin resistance and glucose tolerance, which often becomes the reason for their elimination from therapeutic schemes in patients with disorders of carbohydrate metabolism, so further research in this direction is clearly needed. Analysis of data on the antitumor effect of statins, their ability to sensitize the tumor to treatment with cytostatics showed that the relationship between anthracycline antibiotics and statins is characterized not only by antagonism, but also in some cases by synergism. Despite some adverse effects, statins are among the most promising cardio- and vasoprotectors for the use in anthracycline cardiomyopathy.