**2. Chemotherapy-induced cardiotoxicity (CIC)**

The development of cancer screening methods, early diagnosis, and the widespread use of adjuvant chemotherapy can result in a significantly higher positive response rate in cancer treatment. Cancer drugs destroy cancerous cells in a variety of ways. These actions usually result in cell death (cytotoxicity), but they can also prevent the cell from growing without killing it (cytostatic action) [11].

Chemotherapeutics have a variety of modes of action, including alkylation of DNA, disruption of DNA and RNA synthesis by intercalating between base pairs, inhibition of DNA polymerase, stimulation of apoptosis, inhibition of DNA topoisomerase II, and preventing mitosis via altering tubulin polymerization. With this higher positive response, however, the number of people exposed to chemotherapy's early and late cardiac side effects emerges [12]. A wide range of adverse effects of chemotherapy and radiation on cardiac structure, hemostasis and thrombosis, cardiac dysfunctions and arrhythmias, and toxic effects on the heart have been well-documented [1, 13].

Side effects are common among cytotoxic drugs, notably chemotherapeutic agents; antitumor antibiotics, monoclonal antibodies, tyrosine kinase inhibitors, platinum-based compounds, microtubule inhibitors, vinca alkaloids, antimetabolites, proteasome inhibitors, topoisomerase inhibitors, alkylating agents, corticosteroids, and other drugs. They have the potential to cause long-term morbidity. They are linked to irreversible dilated cardiomyopathy and dose-dependent cardiotoxicity [14, 15].

Anthracyclines, a class of antibiotics derived from Streptomyces spp, have been used to treat a variety of cancers over the last 50 years, including lymphoma, leukemia, bladder cancer, breast cancer, and other metastatic cancers [16, 17]. Cardiotoxicity is a growing concern in clinical oncology due to the increasing use of anthracyclines, the introduction of new antitumor agents with potentially cardiotoxic properties, and the use of combined treatments that may have adverse effects on the heart [18, 19].

Anthracyclines catalyze intracellular oxygen radicals via enzymatic reactions in mitochondria, as well as non-enzymatic iron-mediated free radical reactions which damage DNA. They induce apoptosis in vascular cells and cardiomyocytes by activating caspases and degrading internucleosomal DNA [20]. When compared to other tissues, cardiomyocytes have a 35–40% larger amount of mitochondria. Cardiomyocytes use 90% of the ATP produced by mitochondria [21]. Due to bio-energetic failure, genotoxic stress, and oxidative stress, adenosine monophosphate-activated protein kinase (AMPK) signaling is suppressed during treatment, resulting in increased energy stress and hypertrophy [21]. Serum troponin levels in anthracycline-treated patients are also observed to be higher, indicating cell death [22, 23].

#### *Experimental Model of Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.101401*

Daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin are some of the most commonly used anthracyclines [17]. These drugs have similar effects on cardiotoxicity [24–26]. Following the existence of targeted therapy, doxorubicin is still widely used in cancer treatment today [10, 27]. However, anthracycline's medical use is limited due to dose-dependent and cumulative cardiotoxicity. The clinical efficacy of this drug is restricted due to its side effects, particularly cardiotoxicity when doses exceed 400–700 mg/m<sup>2</sup> for adults and 300 mg/m<sup>2</sup> for children [6, 7, 28]. Doxorubicin cardiomyopathy is more likely at 400 mg/m<sup>2</sup> (5%), at 550 mg/m<sup>2</sup> (26%), and at 700 mg/m<sup>2</sup> , where the risk is as high as 48% [14].

A primary cause of doxorubicin-induced cardiomyocyte damage is assumed to be ROS (reactive oxygen species) generation and lipid peroxidation by inhibition of mitochondrial membrane potential and mitochondrial permeability transition pore [29]. To interfere with DNA replication, doxorubicin inhibits DNA topoisomerase 2-beta (Top2β) whereas a doxorubicin-Top2β DNA complex prevents the repair of damaged DNA and leads to cell death [27, 30, 31]. Doxorubicin also affects adrenergic function and adenylate cyclase inhibition of sarcoplasmic reticulum Ca2+ release, inhibits Ca2+-ATPase activities causing diastolic dysfunction, reduces expression of cardiac-specific genes and down-regulates expression of a variety of cardiac musclespecific proteins including mitochondrial proteins, contractile proteins, sarcoplasmic reticulum proteins [29]. Treatment with doxorubicin induces the immune system to generate a variety of inflammatory mediators (IL-1, IL-6, IL-7, TNF receptor 2, vascular endothelial growth factor/VEGF, matrix metalloproteinases/MMP2); natural killer cells stop functioning, cytotoxic T lymphocytes responses are triggered, and macrophage differentiation is inhibited [32, 33]. Doxorubicin cardiomyopathy increases oxidative stress, which is connected to an increase in Toll-like receptors 2, induces nuclear factor kappa B (NF-κB), and finally leads to apoptosis [34]. There is also an increase in the level of tumor necrosis factor (TNF-α) due to the toll-like receptor 4 [35].

The human epidermal growth factor receptor 2 (ERBB2) is a transmembrane tyrosine kinase receptor that plays in a variety of cellular processes, including cell survival in normal healthy tissue [36]. As a humanized monoclonal antibody, trastuzumab targets ERBB2 on the surface of tumor cells that overexpress ERBB2 [37]. Trastuzumab-induced cardiac damage was detected in metastatic breast cancer trials for the first time. It is the most common chemotherapeutic agent related to left ventricular dysfunction [38]. Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) activity in patients with metastatic colorectal cancer, non-small cell lung cancer, and breast cancer. Although, congestive heart failure (CHF) has been reported in a study, its overall incidence and relative risk are still unknown [39].

Tyrosine kinase (TK) inhibitors (TKI) are molecules designed to target TKs that are overexpressed in cancer cells, but they also inhibit normal variants of tyrosine kinases in non-cancerous cells, which can cause severe side effects such as left ventricular failure [40].

Imatinib is an ATP-competitive small-molecule ABL kinase inhibitor that was developed primarily for the treatment of malignancies such as chronic myeloid leukemia (CML) [41, 42]. It has been shown that imatinib leads to significant mitochondrial damage, including loss of membrane potential, the release of cytochrome C, and markedly reduced energy production with significant declines in ATP concentration, in studies on cultured cardiomyocytes [43, 44]. Other tyrosine-kinase inhibitors such as dasatinib, nilotinib, sunitinib, sorafenib, and lapatinib have been related to drug-induced cardiotoxicity, although the true extent of the damage remains unknown. The literature mentions only a few cases of asymptomatic QT prolongation, pericardial effusion, acute coronary syndromes [45].

Anticancer drugs based on platinum bind to DNA, causing it to crosslink. End result: cancer cells die through apoptosis because of the crosslinks, which interfere with DNA repair and synthesis in the cancer cells. Cisplatin, carboplatin, and oxaliplatin, platinum-based compounds with severe nephrotoxic, neurotoxic, and ototoxic properties, are frequently used in the treatment of human neoplasms [46, 47]. Vascular toxicity, hypertension, dyslipidemia, early atherosclerosis, and coronary artery disease are the most serious late effects of cisplatin-based chemotherapy in patients [48].

Taxanes (paclitaxel, docetaxel, cabazitaxel, Nab-paclitaxel) are microtubule inhibitors (MIT) or mitotic inhibitors that play an important role in mitosis and have lower cardiotoxicity than anthracyclines. Vinca alkaloids such as vinblastine, vincristine, liposomal vincristine, and vinorelbine are also mitotic inhibitors that are used to treat a variety of cancers such as breast, lung, myelomas, lymphomas, and leukemia. As a result, several trials have been conducted to evaluate their use in combination with anthracyclines [49–52].

Antimetabolites such as 5-fluorouracil (5-FU), capecitabine, azacitidine, cytarabine, gemcitabine, methotrexate, hydroxyurea, and pentostatin which are commonly used to treat leukemia, ovarian, breast, gastrointestinal, and other solid tumors, damage proliferating cells during the S phase of mitosis by substituting the normal DNA/RNA building blocks [53]. Endothelial injury followed by thrombosis; energy depletion and myocardial ischemia; coronary arterial spasm following myocardial ischemia; and decreased ability of red blood cells to transfer oxygen leading to myocardial ischemia are all associated with antimetabolite toxicity [54, 55].

Proteasome inhibitors (PI), which primarily function as immunosuppressants and inhibit bone resorption, such as bortezomib, carfilzomib, and ixazomib, are a promising new class of drugs for the treatment of multiple myeloma, and they are also being studied for other types of cancer [56]. As non-proliferative cells with increased proteasome activity, cardiomyocytes are particularly sensitive to proteasome inhibition.

DNA topoisomerases (type I and type II) are the enzymes responsible for DNA unlinking, and play critical roles in a variety of biological processes involving DNA. Several topoisomerase I inhibitors (also known as camptothecins) include irinotecan, topotecan, and camptothecin, while topoisomerase II inhibitors (also known as epipodophyllotoxins) include etoposide, mitoxantrone, and teniposide [57]. Topoisomerase inhibitors cause the release of ROS, lead to DNA breaks and prevent ligase repair. The enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) are antioxidant enzymes in oxidative stress modulation, crucial for efficient removal of ROS. Cardiomyocytes are particularly vulnerable to damage because they have low levels of antioxidant enzymes required to detoxify ROS [58].

Cells are also prevented from reproducing by alkylating agents such as cisplatin, busulfan, mechlorethamine, temozolomide, dacarbazine, streptozocin, which damage their DNA [59].

Following are a few examples of *in vivo* models of chemotherapy-induced cardiotoxicity and protective agents based on the literature;

To explore cardiotoxic effects, animal models are being studied, and therapeutic approaches developed. Because considerable pharmacokinetic and pharmacodynamic data from studies examining the anticancer efficacy of drugs are available, rodents are an attractive model for studying cardiotoxicity.

In the initial periods of cardiotoxicity studies, rabbits were thought to be the standard model. In a study, scientists evaluated the protective effect of ICRF-187 (dexrazoxane, a drug used to prevent anthracycline-induced cardiotoxicity) in rabbits against chronic daunorubicin cardiotoxicity. For the experimental model, twenty-four male white rabbits were divided into four groups (group1; 25 mg ICRF-187/kg and 3.2 mg daunorubicin/kg, group2; daunorubicin (3.2mg/kg), group3;

#### *Experimental Model of Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.101401*

ICRF-187 (25 mg/kg), group4; placebo). They treated animals six times at 3-week intervals over an 18-week period. Significantly different cardiotoxic effects were observed in animals treated only with daunorubicin and those treated only with daunorubicin + ICRF-187. Anthracycline cardiotoxicity was significantly reduced by pretreatment with ICRF-187 [60].

In another study, Zhang et al. divided 50 male Sprague-Dawley rats into three groups for a 15-day experiment: control (saline), doxorubicin (3 mg/kg), and doxorubicin+oxymatrine (12.5, 25, and 50 mg/kg) to detect oxymatrine's protective effects on cardiovascular diseases. Specifically, they found that oxymatrine pretreatment protected against doxorubicin-induced cardiotoxicity in rats' hearts by inhibiting the apoptotic pathway [61].

Zilinyi et al. investigated metformin's (anti-diabetic drug) protective role and its effect on autophagy in doxorubicin-induced cardiotoxicity. In the first group of four Sprague-Dawley rats, doxorubicin (3 mg/kg every second day) was administered intraperitoneally, metformin (250 mg/kg/day) was administered via gavage, and the third group received doxorubicin + metformin, while the fourth group was a control group for two weeks. Doxorubicin-treated myocytes were significantly thinner than those in the control group. Myocyte diameters in the doxorubicin + metformin group were nearly identical to those in the control group. According to the histopathological examination of heart tissue samples, metformin normalized autophagy [62].

In a doxorubicin-induced cardiomyopathy model, Erbaş and his colleagues described the therapeutic effects of liraglutide (LIR), oxytocin, and granulocyte colony-stimulating factor. Four groups of 32 rats were given, respectively, group I; placebo 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (doxorubicin + saline), group II; 1.8 mg/kg/day of liraglutide i.p. (doxorubicin + LIR), group III; 160 μg/kg/day oxytocin i.p. (doxorubicin + OX), group IV; 100 μg/kg/day filgrastim i.p. (doxorubicin + G-CSF (Granulocyte colony-stimulating factor)). It was revealed through the study's findings inflammatory activity and improved tissue integrity were found to be decreased in response to oxytocin treatment. Besides, LIR reduces levels of proinflammatory cytokines, lipid peroxidation products, troponin T, pro-BNP levels, and CASPASE-3 in doxorubicin-treated rats [63].

Arsenic trioxide and imatinib mesilate cardiotoxicity were examined in male Wistar rats. In the experiment, for ten days, arsenic trioxide (5 mg/kg) and imatinib mesilate (30 mg/kg) was given intraperitoneally and orally, respectively. As a result, the cardiac tissue of the combination-treated group showed fibroblastic proliferation, myocardial disorganization, and myocardial necrosis [64].

According to a study by Saleh et al., tadalafil (Tad) might protect against cardiac and vascular damage caused by the chemotherapy drug cisplatin (CDDP). Seventy-two male albino rats were divided into four groups: the control group, the CDDP (4 mg/kg) i.p. group, the Tad (0.4 mg/kg BW Tad i.p. daily) group, and the Tad +CDDP (0.4 mg/kg BW Tad i.p. + 4 mg/kg BW CDDP i.p) group. In the heart homogenate sample from CDDP treated rats, Tad was able to reduce blood pressure, heart rate, and levels of cardiac troponin, malondialdehyde (MDA), while increasing levels of reduced glutathione (GSH) and nitric oxide (NO) [65].
