A journey in doxorubicin-induced cardiotoxicity with emphasizing on the role of Connexin 43 and Sirtuin-3

Cancer has become a major health problem worldwide. The reported incidence of new cancer cases is estimated at 19.3 million, with a mortality rate of 10 million in the world in 2020. There are some approaches for cancer treatment such as chemotherapy, neoadjuant surgery, hormone therapy, and radiotherapy. Chemotherapy is an aggressive form of chemical drug therapy meant to destroy rapidly growing cells in the body. It’s usually used to treat cancer, as cancer cells grow and divide faster than other cells. On the other hand, chemotherapy means consuming anti-neoplastic drugs, alone or in combination. However, these drugs can cause damages to the normal cells and have many side effects. The most common side effects are allergic reactions, hair loss, urination disturbances, heart damages, bone marrow suppression, vomiting, and kidney injury. Anthracyclines are commonly used in chemotherapy; especially doxorubicin is the most widely used drug of this family. Doxorubicin, the anthracycline antibiotic, was first produced from Streptomyces peucetius var. caesius in 1960. Doxorubicin is represented as one of the most effective broad-spectrum anti-cancer agent. It is determined widely efficient against various types of cancers, including solid malignancies (bladder, breast, lung, etc.) and hematologic tumors (Hodgkin’s disease and non-Hodgkin’s lymphomas, pediatric leukemia). The primary mechanism of action of doxorubicin involves the drug’s ability to intercalate within DNA base pairs, causing breakage of DNA strands and inhibition of both DNA and RNA synthesis. Also, it inhibits the enzyme topoisomerase II, causing DNA damage and induction of apoptosis. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication. When combined with iron, doxorubicin also causes free radical-mediated oxidative damage to DNA, further limiting DNA synthesis. Iron chelators, such as dexrazoxane, may prevent free radical formation by limiting binding of doxorubicin with iron. The most dangerous side effect of doxorubicin is cardiomyopathy, leading to congestive heart failure. Doxorubicin-induced cardiotoxicity starts from myocardial cell injury; and is followed by left ventricular damage. It is assumed that this drug has many cytotoxic mechanisms. The cardiac side effects of doxorubicin during a chemotherapy regimen can be acute, chronic, or even gradually progressive and persistent after termination of doxorubicin therapy. The incidence of doxorubicin-induced cardiotoxicity rises with the escalation in total cumulative dose of doxorubicin during a day or a treatment cycle. Cardiotoxicity induced by doxorubicin is very common and there is no reliable and absolute treatment for this problem. Unfortunately, there are currently a few medications for the treatment of doxorubicin-induced cardiotoxicity in clinical setting. Extensive basic and clinical researches have been done to discover preventive treatments. Various studies sought to explain the underlying cellular mechanism that participates in the manifestation of this medication’s undesirable effects. Disruption of normal mitochondrial function, decreased amount of antioxidant defense (catalase, superoxide dismutase, and peroxidase), production of reactive oxygen species (ROS), iron free radical formation, oxidative stress pathways, activation of inflammatory cascade and inflammatory factors including nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α), and imbalance of intracellular ions homeostasis are involved in phathophysiology of doxorubicin-induced cardiotoxicity. Gap junctions are the most important structures in cardiomyocytes. The presences of gap junctions in the cardiomyocytes are necessary for conduction of impulses and maintenance of the integrity of cardiac cells contractions and excitation. Gap junctions are aggregates of intercellular channels that facilitate direct cell–cell interactions and intercellular transmission of molecules and ions. Electrical connection between cardiomyocytes and maintenance of the normal cardiac rhythm are mediated by gap junctions, and these junctions consist of groups of membrane channels that directly link the cytoplasmic parts of nearby cells. Each gap‐junctional channel is constructed from connexins. The most abundant isoform of connexin in the mammalian cardiac cells is connexin43 (Cx43), while other types of connexins are also expressed. Cx43 generally localizes in gap junctions, but has also been detected in mitochondria, and it is considered vital for cardioprotection. Mitochondrial-Cx43 has a crucial role in mitochondrial permeability under conditions of calcium overload and oxidative stress. Additionally, Cx43 also participates in other cellular functions such as cell growth, differentiation and death/survival signaling, but the involvement of Cx43 in these functions may be partially or fully independent of its role in intercellular communication. Administration of doxorubicin induces alterations in Cx43 expression and distribution. Therefore, electrical signal conduction between cardiomyocytes, intracellular calcium homeostasis, and mitochondrial function are disturbed. As a result, a part of the cardiotoxic effects of doxorubicin is exerted by affecting function of Cx43. Elevation in the level of Cx43 in the intercalated discs could reduce doxorubicin cardiotoxic effects such as cardiomyocytes calcium overload and ECG abnormities. Sirtuins are a well-known family of proteins found in most classes of the organisms, including mammals. Sirtuins have many vital roles in mammalian physiology, and they may provide new targets for treating diseases associated with aging and perhaps increasing lifespan. Seven mammalian sirtuins, SIRT1–7, have been identified. Sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3) are essential for the regulation of metabolic processes in mammalian. Various metabolic disorders are related to SIRT1 and SIRT3 deficiencies. The kidney, brain, and heart have highest tissue levels of SIRT3. It is localized in the mitochondrial matrix, and it is necessary for enzymatic activity and expression of many mitochondrial proteins. Moreover, mitochondrial sirtuins reduce degree of myocardial ischemia-reperfusion injury, expansion of cardiac hypertrophy, and heart failure. Therefore, elevation in cardiac tissue levels of sirtuins for improvement of myocardial mitochondrial energetics is a novel approach in several cardiac disorders. Sirtuins are activated by low energy levels and stimulate energy production through their activation of transcription factors and enzymatic regulators of cardiac energy metabolism. Mitochondrial sirtuins preserve mitochondrial function by increasing mitochondrial metabolism, inhibiting ROS generation, decreasing apoptosis, controlling the quality of mitochondria, and increasing autophagy. Moreover, doxorubicin interferes with myocardial energetics; thus a hopeful approach to reduce cardiotoxic effects of doxorubicin may be to target mitochondria and improve metabolic function. Because of the importance of sirtuin nd CX43 in the cardiac function, the aim of this study was to investigate the role of connexins and sirtuins in doxorubicin-induced cardiotoxicity.