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

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Abstract—

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.

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Funding

The work was carried out within the framework of funding under the State assignment of the Program “Cellular and molecular mechanisms of damage and remodeling of tissues and organs in metabolic disorders and toxic effects, development of technologies for stimulating cytoprotective reactions and tissue-specific reparative regeneration.” The scientific theme code: 0535-2019-0028, the State registration number AAAA-A19-119020790017-9.

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  1. Institute of Molecular Pathology and Pathomorphology, Federal Research Center of Fundamental and Translational Medicine, ul. Timakova 2, 630117, Novosibirsk, Russia

    N. V. Tursunova, M. G. Klinnikova, O. A. Babenko & E. L. Lushnikova

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  1. N. V. Tursunova
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  2. M. G. Klinnikova
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  3. O. A. Babenko
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Correspondence to N. V. Tursunova.

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Translated by A. Medvedev

Abbreviations used: AIF—apoptosis inducing factor; Akt—RAC-alpha serine/threonine-protein kinase; AMPK—AMP-activated protein kinase; AP-1—activator protein-1; Apaf-1—аpoptotic protease activating factor 1; ER—endoplasmic reticulum ; ET-1—endothelin; Fas/Fasl—the system of the Fas receptor, apoptosis antigen 1 and its Fasl ligand; FPP—farnesyl pyrophosphate; GAPs—GTPase-activating proteins; GEFs—ganine nucleotide exchange factors; GGPP—geranylgeranyl pyrophosphate; GLUT-1, GLUT-4—glucose transporters-1, -4; GSH—reduced glutathione; GSK-3b—glycogen synthase kinase 3 beta; HbA (1с)—glycated hemoglobin; HIF-1—hypoxia-inducible factor-1; HMGB1—high-mobility group protein B1; HMG-CoA reductase—hydroxymethylglutaryl coenzyme A reductase; ICAM-1—inter-cellular adhesion molecule 1; IL-1, -2, -6, -8, ‑18—interleukins; LDL—low-density lipoprotein; LFA-1—lymphocyte function-associated antigen 1, containing an allosteric site termed as the lovastatin site (L-site); Lp-PLA2—lipoprotein-associated phospholipase A2; LOX-1—lectin-like oxidized low-density lipoprotein receptor-1; МАРК—mitogen-activated protein kinase (mitogen-activated protein kinases; JNK, ERK, p38 MAPK); МСР-1—monocyte chemoattractant protein-1; MMPs—matrix metalloproteinases; mTOR—mammalian target of rapamycin; NFAT-1,-2,-4—nuclear factor of activated T-cells; NF-κB—nucleus factor kappa B; NO—nitric oxide; NOO–—peroxynitrite; NOS—nitrogen oxide synthase: (еNOS—endothelial nitrogen oxide synthase; iNOS—inducible nitrogen oxide synthase); Nrf2—nuclear factor erythroid 2‑related factor 2, nuclear E2-related factor 2; oxLDL—oxidized low-density lipoprotein cholesterol; p91phox, p22phox, p67phox, p47phox, p40phox—cytosolic proteins, subunits of NAD(P)H-oxidase; pCAMK II—calmodulin-dependent protein kinase II; PI3K—phosphoinositide 3-kinase; PPARs—peroxisome proliferator-activated receptors; PTEN—phosphatase and tensin homolog; Rho, Cdс42, Rac1, RhoA (Rac2)—monomeric G-proteins of the GTPase family; Rho-GTPases—Ras-homologous GTPases; RNS—reactive nitrogen species; Rock – RhoA-associated protein kinase; ROS—reactive oxygen species; S6K1—ribosomal protein kinase S6 beta-1; SERKA—Ca2+-ATPase; SIRT1—deacetylase sirtuin 1; SOD—superoxide dismutase; TGF-β1—transforming growth factor beta; TLR2, TLR4, TLR9—Toll-like receptors-2, -4, -9; TNFα—tumor necrosis factor α ; Top II—topoisomerase II; VCAM-1—vascular cell adhesion molecule 1; VEGF—vascular endothelial growth factor; VEGFR2—vascular endothelial growth factor receptor 2.

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Tursunova, N.V., Klinnikova, M.G., Babenko, O.A. et al. Molecular Mechanisms of the Cardiotoxic Action of Anthracycline Antibiotics and Statin-Induced Cytoprotective Reactions of Cardiomyocytes. Biochem. Moscow Suppl. Ser. B 15, 89–104 (2021). https://doi.org/10.1134/S1990750821020116

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