Cyclophosphamide is an anticancer drug with antitumor properties that is commonly used in humans for a range of neoplasms [12]. However, multiple reports have indicated that, in addition to having tumor-selective properties, cyclophosphamide has a slew of highly hazardous adverse manifestations (Figure 1), the most serious of which is cardiotoxicity [13].

Cyclophosphamide is activated by the cytochrome P-450 (CYP) enzyme in the liver, which transforms it into 4-hydroxycyclophosphamide. Aldo cyclophosphamide (AldoCY) and 4-hydroxycyclophosphamide are in equilibrium. AldoCY may be oxidized by aldehyde dehydrogenase 1 (ALDH1) to the inactive metabolite o-carboxymethylphosphoramide mustard (CEPM) or beta eliminated through a chemical mechanism that decomposes to produce cytotoxic phosphoramide mustard (PM) and the byproduct acrolein, depending on the cell type [14]. The antineoplastic activity of cyclophosphamide is due to the presence of phosphoramide mustard, which is the therapeutic metabolite in the active form present in cyclophosphamide, and it shows DNA alkylation activity, whereas acrolein, the other metabolite of cyclophosphamide, has the ability to interfere with the antioxidant system, further causing the generation of strongly active oxygen-free radicals, superoxide radicals, and hydrogen peroxide [15]. These free radicals are implicated in several enzyme inhibitions, lipid peroxidation, as well as membrane injury [16]. The generation of free radicals mediates oxidative stress associated with cyclophosphamide treatment witnessed by the following pathways.

Doxorubicin (DOX) is an anthracycline antibiotic that was first derived from a bacterium called Streptomyces peucetius in the early 1960s and was first used as a cytotoxic drug in 1969 [36,37]. It is a highly successful chemotherapeutic medication for solid tumors, soft-tissue sarcoma, breast cancer, Hodgkin’s disease, Kaposi’s sarcoma, acute lymphoblastic leukemia, pediatric leukemia, lung cancer, lymphomas, and various metastatic malignancies [2,38,39]. The drug’s utility is limited owing to its large number of side effects, such as the suppression of the hematopoietic system, gastrointestinal disturbances, and baldness, with cardiac damage being the most dangerous [40,41,42].

The advanced conditions of cancer patients treated with repeated doses of doxorubicin for more than a month developed severe symptoms of myocardial toxicity with a prevalent rate of more than 30%. The wide spread of symptoms ranged from ventricular failure, a decrease in QRS segment, cardiac dilatation, tachycardia (150 beats/min), and hypotension (blood pressure 70/50 mmHg) [43]. The patients were unresponsive to inotropic drugs and mechanical circulatory assist devices. Several biomarker levels such as creatine phosphokinase, serum glutamic-oxaloacetic transaminase, and lactate dehydrogenase were also elevated. The histopathological examination reported decreased myofibrils, altered structure of the sarcoplasmic reticulum, vacuolization of the cytoplasm, mitochondrial inflammation, and elevated numbers of lysosomes [44,45]. Different experimental animals such as rats, mice, and rabbits treated with doxorubicin also reported similar symptoms of myocardial toxicities. The experimental animals in several studies in a reproducible manner showed the symptoms of cardiomyopathy and heart failure with the exposure of doxorubicin [46,47].

Multiple processes are involved in doxorubicin-induced cardiotoxicity, which has been linked to increased myocardial damage due to oxidative free radicals, as well as lower levels of sulfhydryl groups and antioxidants. In addition to myofibrillar deterioration and intracellular calcium dysregulation, doxorubicin-induced cardiac toxicity is known to cause myofibrillar deterioration [48,49]. Mitochondrial biogenesis is also hypothesized to be actively involved in doxorubicin-mediated cardiac damage due to its potential to stimulate the cell death pathway while blocking topoisomerase 2β [50,51]. Alterations in gene expression of the cardiac system, such as the expression of muscle-specific genes (cardiac actin, myosin light chain, and muscle creatine kinase), are shown to decrease in response to doxorubicin exposure in acute doxorubicin cardiotoxicity [52,53]. Endothelial dysfunction, an activated ubiquitin protease system, autophagy, and cell death collectively participate in doxorubicin-induced cardiotoxicity, as do NO release, impaired adenosine triphosphate (ATP) levels, iron regulatory protein (IRP) production, and augmented inflammatory mediator release [54,55].

This is a monoclonal antibody that is employed for the treatment of breast cancer patients who concurrently have an elevated human epidermal growth factor receptor 2 (HER2, also known as ErbB-21) level [88]. While therapeutic therapy with trastuzumab is reported to reduce morbidity and mortality in breast cancer patients, there are serious cardiac adverse effects that need to be checked [89,90]. HER2 is an important target for breast cancer and, similarly, a prime target for trastuzumab [91]. However, some mutant mouse models have documented that there are also some important roles regulated by ErbB-2 genes, such as in postnatal cardiomyocyte function and development [92]. Similarly, evidence suggests that ErbB-2 genes are involved in the normal functioning of the myocardium, which includes the involvement of a number of key pathways (such as phosphoinositide 3-kinase, mitogen-activated protein kinase, and focal adhesion kinase) that are required for cardiomyocyte maintenance, and the inhibition of apoptosis. Therefore, the blockade of ErbB signaling by trastuzumab could have been a major reason for its ability to induce cardiotoxicity [93,94].

However, the risk of developing trastuzumab cardiotoxicity has been seen to increase in patients who receive concurrent anthracycline therapy [90,95,96]. When trastuzumab suppresses ErbB2 signaling, it was reported that it further accelerates the anthracycline’s ability to induce sarcomeric protein breakdown, increasing the chances of cardiac toxicity and heart failure [97]. The pathogenesis and molecular mechanism involved in trastuzumab-induced cardiotoxicity are given in Figure 2 [98].

5-fluorouracil (5-FU) is a pyrimidine analogue chemotherapy medication employed in the treatment of a number of cancer types, including colorectal, breast, gastric, pancreatic, prostate, and bladder cancers, among others [99,100]. Myelosuppression, diarrhea, stomatitis, nausea, vomiting, and baldness are common side effects of the medication. Furthermore, 5-FU has been linked to cardiotoxicity, which includes myocardial infarction, cardiac arrhythmias, altered blood pressure, left ventricular failure, cardiac arrest, and sudden death [99]. The potential mechanisms involved in 5-FU-induced cardiotoxicity are given in Figure 3 [101]. Angina is noticeable mostly during infusions, and occasionally it is delayed until a few hours after 5-FU application. The incidence of angina associated with the use of 5-FU ranges from 1.2 to 18 percent [102,103,104,105]. Cardiotoxicity that is severe or life-threatening or ventricular arrhythmias, on the other hand, are far less common, with an incidence of about 0.55 percent [106]. When compared to anthracyclines, cardiac adverse effects of 5-FU are rare, with an incidence of 1.2–7.6%, and life-threatening cardiotoxicity of 5-FU has been documented in less than 1% of cases [107]. Though the exact processes of 5-FU-mediated cardiac toxicity are yet unknown, spasm of the coronary artery is suggested as a hypothesis [64]. Ultrasound and angiography have been used in several investigations to show that 5-FU infusion causes both coronary and brachial artery vasospasm. Patients with coronary vasospasm may have ECG findings suggestive of coronary occlusion, such as ST-segment elevation and biochemical changes in myocardial injury with increased troponin. As a result, it is recommended that when 5-FU is given to cancer patients, a high index of suspicion for probable cardiac toxicity be maintained [108].

Cisplatin, commonly known as cis-di ammine dichloroplatinum (CDDP), is a highly effective chemotherapy drug [109]. In diseases such as ovarian and cervical cancer and testicular cancer, it is used alone or in combination regimens [110]. However, due to adverse effects, including toxicities to the kidney, liver, and gastrointestinal disturbances, cisplatin’s clinical use is restricted. Despite these side effects, many survivors of cisplatin treatment may develop acute or chronic cardiovascular problems, which can negatively impact their quality of life [111]. CDDP-induced cardiotoxicity has been linked to ventricular and supraventricular arrhythmias, occasional sinus bradycardia, alterations in electrocardiography, occasional total atrioventricular block, and congestive heart failure. With cisplatin-based chemotherapy, oxidative stress is considered as a major reason for cardiac toxicity [112]. It has also been shown that cisplatin-based chemotherapy causes a decrease in the concentration of different antioxidants in patients. It may also cause ROS generation by accumulating in mitochondria [113]. However, it has been documented that all of these factors collectively lead to congestive heart failure and sudden cardiac death. Table 1 summarizes the adverse cardiotoxic consequences of chemotherapy [114].

With cancer progression, initially, the body’s immune system prevents tumor outgrowth. However, cancer cells can escape the various pathways that provide immunologic antitumor responses, and such pathways include immune system inhibitory pathways such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death ligand 1 (PD-L1), and programmed cell death 1 (PD-1) (natural checkpoints that dampen the antitumor responses of T cells). Therefore, various studies were carried out to determine if by stimulating an antitumor immune response in cancer patients, cancer could be fought better. Since then, immunotherapy came into existence, and this is divided into passive immunotherapies such as monoclonal antibodies, checkpoint inhibitors, cytokine therapy, bispecific T cell engager and antitumor vaccines or adoptive T cell transfer, which dramatically improved outcomes for wide varieties of cancer, among which adoptive T cell therapy and immune checkpoint inhibitors are most widely used and are used as longer duration therapy. However, having the benefit of activated immune response came with a price, as both the therapies have been reported to cause various cardiovascular complications such as hypotension, arrhythmia, left ventricular dysfunction, myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, and cardiogenic shock [115,116,117,118,119].