The anthracyclines, such as doxorubicin, daunorubicin, and epirubicin, are a class of broad-spectrum anticancer drugs extracted from Streptomyces bacterium. These compounds are used to treat different adult and pediatric hematologic cancers, such as leukemia and lymphomas, as well as many solid tumors, including breast, stomach, uterine, ovarian, bladder and lung cancers. However, anthracyclines are associated with a dose-dependent risk of cardiomyopathy and HF [reviewed in (2–7)]. Specifically, in the absence of risk factors, doxorubicin is tolerated up to a cumulative dose of 300 mg/m², with a rate of HF of less than 2% (18). Retrospective studies have shown that an estimated 3–5% of patients, without other risk factors, would experience doxorubicin-related HF at a cumulative dose of 400 mg/m², increasing at 7–26% and 18–48% for a dose of 550 and 700 mg/m², respectively (18, 19). Based on these evident cardiotoxic effects, high-dose treatments with anthracycline are no longer administrated, but sub-acute and chronic cardiac effects are still a clinical problem. The use of second-generation analogs of doxorubicin, namely epirubicin or idarubicin, exhibits improvements in their therapeutic index, but the risks of inducing cardiomyopathy are not abated [reviewed in (6)]. Mitoxantrone, which is an anthracenedione, an anthracycline analog, can also damage the cardiac muscle cells, thus resulting in cardiac dysfunction (20) [reviewed in (21, 22)].

Importantly, a large body of evidence indicates that cardiomyopathy develops at lower doses of anthracyclines in the presence of risk factors, including hypertension, arrhythmias, coronary disease, combination with other anticancer agents as well as genetic predisposition to cardiotoxicity [reviewed in (17, 23, 24)]. In this regard, among the genetic factors increasing the susceptibility to anthracycline-induced cardiotoxic effects, the role of specific single-nucleotide polymorphisms (SNPs) is emerging [reviewed in (24, 25)]. Indeed, heritability analysis on multiple cell lines unveiled SNPs from 30 genes giving a greater predisposition to daunorubicin-induced cardiotoxicity (26). Specifically, several SNPs associated with anthracycline cardiotoxicity affect genes involved in anthracycline metabolism, transport, or downstream cytotoxic effects. For example, studies on pediatric cohorts enlightened polymorphisms in CBR1 and CBR3 genes (encoding for carbonyl reductases) associated with enhanced cardiotoxicity susceptibility in children with cancer (27), polymorphisms in ABCC1 and ABCC5 genes (encoding for ATP-binding cassette transporters) associated with increased anthracycline-induced cardiac dysfunction in acute lymphoblastic leukemia patients (28, 29), polymorphisms in SLC22A gene (encoding for a solute carrier) (30), as well as polymorphisms in genes playing a role in iron homeostasis (31), and others [reviewed in (25, 32)]. Oppositely, SNPs in endothelial nitric oxide synthase (NOS3) gene have been reported to be cardioprotective in patients upon a high dose of doxorubicin (29).

Cardiac injury after anthracycline administration occurs with every dose, as documented by the analysis of cardiac-biopsy specimens a few hours after a single dose of anthracycline [reviewed in (7)]. Although the vast majority (98%) of cases of anthracycline cardiotoxicity being detected within the first year after completing the treatment (33), anthracycline-induced cardiotoxicity can also manifest months to years after completing chemotherapy (33). From a pathophysiological point of view, anthracyclines were suggested to induce cardiotoxicity through cardiomyocyte-intrinsic mechanisms as well as other mechanisms involving other cardiac cell types (Figure 1). Importantly, anthracycline-induced cardiac damage may be permanent due to cardiomyocyte death through several biological processes, including apoptosis, autophagy, necrosis, necroptosis, pyroptosis, and ferroptosis [reviewed in (34)]. In this regard, the alteration of mitochondrial function and integrity emerged as a distinctive feature of anthracycline-induced cardiomyopathy [reviewed in (7, 34–39)]. Mitochondria network is well developed in the cardiac muscle, occupying 36–40% of the cardiomyocyte volume and producing around 90% of the cellular energy [reviewed in (40–43)]. Among the complex underlying molecular mechanisms involved in anthracycline-induced mitochondrial dysfunction is worth to mention the formation of reactive oxygen species (ROS), iron-catalyzed formation of free radicals, lipid peroxidation, and cardiolipin sequestering (44, 45) [reviewed in (6, 14, 34, 38)]. In this regard, in cardiac mitochondria, anthracyclines can be reduced by NAD(P)H-oxidoreductases and converted to unstable metabolites, such as doxorubicin-semiquinone radicals, which can react with molecular oxygen (O₂), producing superoxide anion-free radicals and hydrogen peroxide (O2- and H₂O₂) (46) [reviewed in (37)]. ROS generated by anthracyclines affect the activity of many mitochondrial enzyme complexes, such as NOSs, NAD(P)H oxidases, catalase, and glutathione peroxidase (GPx), leading to DNA, protein, and lipid damage, and consequently to cardiomyocyte death [reviewed in (39, 47, 48)]. Moreover, anthracyclines, such as doxorubicin, have been reported to impair cardiac iron homeostasis, resulting in its overload in the cardiac tissue [reviewed in (14, 49, 50)]. Accordingly, patients with anthracycline-induced cardiac dysfunction exhibit higher iron levels in cardiac mitochondria, compared to healthy individuals or patients suffering from anthracycline-independent cardiac dysfunction (44). Doxorubicin can, in fact, chelate the free intracellular iron and form iron-doxorubicin complexes, which, in turn, are able to react with O₂, further increasing the generation of ROS [reviewed in (4, 14, 49, 50)]. In addition, anthracyclines can directly interfere with the main iron-transporting/-binding proteins. For example, doxorubicin can impair cellular iron mobilization, resulting in its accumulation within ferritin (51), and can reduce the expression of the mitochondrial iron exporter ABCB8 (44). Recent studies have also focused on the detrimental role of mitochondrial iron-doxorubicin complexes triggering cardiomyocyte ferroptosis, a kind of programmed cell death dependent on iron and induced by lethal lipid peroxidation (52) [reviewed in (50)]. In this regard, doxorubicin-induced cardiotoxicity in mouse models was shown to be consequent to a decrease in the expression levels of glutathione peroxidase 4 (GPx4), which is a scavenger for lipid peroxides, in turn inducing peroxidation of unsaturated fatty acids and lipids (52). Anthracyclines are also linked to mitochondria damage because of their high affinity to cardiolipin, a mitochondrial membrane phospholipid that is involved in apoptotic pathways [reviewed in (35, 53)]. Mechanistically, doxorubicin sequesters cardiolipin avoiding its anchorage to cytochrome C or lipid-protein interfaces, thus contributing to mitochondrial dysfunction and ROS formation (54) [reviewed in (35, 53)]. Along with the impaired cardiac mitochondrial function, anthracyclines have been demonstrated to alter the structural integrity of mitochondria. Indeed, it has been reported that doxorubicin stimulates the receptor-interacting protein 3 (RIPK3)-induced activation of Ca²⁺-calmodulin-dependent protein kinase (CaMKII), thus triggering the opening of mitochondrial permeability transition pore (MTPT), and ultimately inducing necroptotic cardiomyocyte death (55).

Several lines of evidence have suggested that nuclear damage induced by topoisomerase 2 (Top2) is another pivotal event in anthracyclines’ cardiotoxic effects (45, 56) [reviewed in (4, 6)]. Specifically, doxorubicin intercalates into DNA and interacts with both Top2-alpha (Top2α) and Top2-beta (Top2β), which are enzymes responsible for managing DNA tangles and super-coils. Top2α is highly expressed in proliferating cancerous cells but not in quiescent tissues; therefore, it is considered one of the key molecular targets of anthracycline anti-tumoral effect (56). Cardiomyocyte toxicity stems from the fact that doxorubicin interacts with cardiac Top2-β, the only isoform expressed by adult mammalian cardiomyocytes. Consequently, the Top2β-doxorubicin-DNA complex induces DNA double-strand breaks (DSBs), ultimately promoting cardiomyocyte death (45, 56).

Tumor protein P53 (p53) has also been implicated in anthracyclines’ cardiotoxic response, although its involvement is currently controversial. Indeed, it has been reported that DNA breaks, induced by acute doxorubicin administration, lead to activation of the DNA damage response (DDR) network, in turn activating p53, which ultimately promotes the apoptotic cascade (57) [reviewed in (58)]. Moreover, in response to cell stress, p53 was shown to accumulate in the cytosol and to localize in mitochondria, triggering a series of death-events related to mitochondrial dysfunction, such as the permeabilization of the mitochondrial outer membrane (MOMP), the release of cytochrome C, the opening of the mitochondrial permeability transition pore (PTP), the impairment of mitochondria, and the production of ROS (59–63). Mice depleted for p53 exhibit a less impaired mitochondrial integrity and reduced cardiac dysfunction following doxorubicin treatment [reviewed in (5)]. In addition, doxorubicin-activated p53 has been shown to contribute to metabolic derangement by inhibiting mitophagy events (45) [reviewed in (4)]. As a result of cytosolic accumulation, p53 binds Parkin and abrogates its translocation to damaged mitochondria and their subsequent clearance by mitophagy (64) [reviewed in (5)]. These results support p53 as a key player in anthracycline-related cardiomyopathies (61, 62) [reviewed in (4)]. Nevertheless, other studies unveiled opposite effects depending on the dosage and timing of doxorubicin-induced cellular stress. Indeed, upon low doses of doxorubicin, which more closely recapitulate the clinical settings, it has been reported a protective role of p53, counteracting the late-onset cardiomyopathy and without activation of p53-dependent cell death cascades (65, 66).

In addition to cardiomyocyte-intrinsic mechanisms, anthracyclines exhibit a wide range of maladaptive effects on other cardiac populations, including fibroblasts, endothelial cells, vascular smooth muscle cells, and immune cells [reviewed in (67)]. In particular, doxorubicin administration was shown to increase endothelial cellular permeability, in turn causing edema formation [reviewed in (67)], to induce ROS-dependent activation of transforming growth factor beta (TGFβ) signaling, in turn triggering myofibroblast activation and collagen deposition [reviewed in (67)], and to induce the activation of the innate immune system and inflammatory response [reviewed in (67)]. Overall, these events were suggested to lead to pathological left ventricular remodeling [reviewed in (67)].

Fluoropyrimidines exert the second most common cause of chemotherapy-induced cardiotoxicity [reviewed in (68–74)]. This antimetabolite drug class, which includes 5-fluorouracil (5-FU) and its prodrug capecitabine, is incorporated into DNA or RNA, thus acting as cytostatic agent for the clinical treatment of colorectal, breast, gastric, pancreatic, prostate, and bladder cancers [reviewed in (74)]. Fluoropyrimidines are generally well tolerated; nevertheless, 1–18% of the patients receiving fluoropyrimidines experiences cardiovascular toxicity [reviewed in (69–71, 73–75)]. Cardiovascular side effects associated with fluoropyrimidines include a generally reversible coronary artery spasm and myocardial ischemia, although cardiomyocyte death and loss may occur as consequence of coronary artery thrombosis and myocardial infarction [reviewed in (69, 75, 76)], as well as directly through cardiomyocyte-intrinsic mechanisms (77). These adverse effects were suggested to be mediated by vascular smooth muscle cells, erythrocytes, endothelial cells as well as directly by cardiomyocytes (Figure 2). From a molecular point of view, 5-FU was reported to induce protein kinase C-mediated vasoconstriction in vascular smooth muscle cells (78) [reviewed in (69)]. 5-FU was also shown to reduce the oxygen transport capacity of erythrocytes, inducing relative ischemia of the myocardium (79). 5-FU administration was also suggested to induce increased ROS production in endothelial cells, leading to cell senescence and death (77), in turn triggering a procoagulant state and acute thrombotic events [reviewed in (69)]. Finally, direct cardiomyocyte toxicity after fluoropyrimidine administration has also been suggested. Indeed, 5-FU has also been demonstrated to favor ROS production and to induce cardiomyocyte apoptosis and autophagy (77).

Taxanes, such as paclitaxel, are antimitotic agents that stabilize microtubules in the mitotic spindle, thus blocking cell cycle progression. These chemotherapy drugs are widely employed in cancer treatment, including breast, lung, and ovarian cancers. However, significant toxicities limit the effectiveness of taxane-based treatment regimens (80). Taxane administration is reported to induce cardiotoxic events in 3–20% of the patients (81, 82) [reviewed in (83–85)]. Taxane-induced cardiotoxic effects include QT interval prolongation, followed by bradycardia and atrial fibrillation (82). Because taxane-induced cardiotoxicity appears to be mild in most cases and reversible upon discontinuation of the therapy, no specific agents are recommended for their management [reviewed in (86, 87)].

The underlying cellular and molecular mechanisms of taxane-induced cardiotoxicity are unclear; however, a few hypotheses have been proposed (Figure 3). Among them, hypersensitivity reaction with a massive histamine release and consequent disturbance of the conduction system and arrhythmia has been proposed (82). Hence, the administration of anti-inflammatory (glucocorticoids) and anti-histamine drugs (histamine receptor blockers), is suggested as prophylactic therapy for the management of cardiac anaphylaxis induced by taxanes [reviewed in (37, 88–90)]. Another hypothesis is cardiomyocyte damage through the drug’s actions on subcellular organelles (82). In this regard, taxanes were suggested to increase ROS production by cardiomyocyte mitochondria, the opening of mitochondrial permeability transition pore and the collapse of mitochondrial membrane potential (91).

Among taxanes, paclitaxel has been shown to exacerbate anthracycline-induced toxicity. Indeed, combined treatment with paclitaxel and doxorubicin augmented HF events (92) and increased histopathological alterations of cardiac tissue, with extensive necrosis (93). This effect was suggested to derive from a pharmacokinetic interference of doxorubicin elimination by paclitaxel [reviewed in (94)]. No interaction between doxorubicin and other taxanes (such as docetaxel) has been reported; in line, docetaxel showed no increase in cardiac toxicity when combined with doxorubicin [reviewed in (94)].

Alkylating drugs, such as cisplatin, cyclophosphamide, ifosfamide, mitomycin, are crosslinking agents inducing ROS production, DNA damage and apoptosis in cancer cells [reviewed in (95)]. Cisplatin is mostly used in combination with other chemotherapy drugs to overcome drug-resistance and reduce toxicity [reviewed in (95)]. Cisplatin-based chemotherapy has been reported to cause cardiovascular diseases, particularly myocardial infarction and angina, in a range of 7–32% of patients (96) [reviewed in (97)]. In patients treated with cisplatin, a long-term unfavorable cardiovascular risk profile was observed, with hypercholesterolemia, hypertriglyceridemia, hypertension and insulin-resistance evaluated after more than 10 years from remission (98). The cardiotoxic effects of alkylating agents may be permanent and a few cellular and molecular mechanisms were suggested to contribute to these processes (Figure 4). Indeed, cisplatin administration has been linked with thromboembolic events associated with platelet aggregation and vascular damage (99) [reviewed in (87)], in turn resulting in cardiomyocyte degeneration and necrosis. The increased platelet aggregation was suggested as a direct consequence of cisplatin on the activation of the arachidonic pathway in platelets [reviewed in (87)]. The endothelial capillary damage was suggested to derive from a cisplatin-dependent increase in oxidative stress (99). Indeed, cisplatin has also been shown to induce oxidative stress in myocardial tissue, with decreased activity of glutathione and antioxidant enzymes (100, 101). The consequence of cisplatin-induced endothelial injury was suggested to be the extravasation of proteins, erythrocytes, and toxic metabolites, in turn causing damage to the myocardium (99). Finally, cisplatin has also been suggested to activate NF-κB in the cardiac tissue (101), in turn increasing the expression of proinflammatory chemokines and cytokines (102). This mechanism was proposed to result in cardiac remodeling (101), and extensive degeneration and fragmentation of cardiac muscle fibers (102).

The alkylating agent cyclophosphamide at high doses can cause hemorrhagic cell necrosis and may lead to HF; however, with the lower doses currently used, these side effects are infrequent (103).

Growth factor receptors of the ERBB family (EGFR/ERBB1, ERBB2, ERBB3, and ERBB4) play a key role in the development and progression of a variety of solid cancers [reviewed in (104–106)]. After the binding of soluble ligands, ERBB kinase receptors arrange in homo- or heterodimer complexes, which activate the tyrosine kinase activity and the consequent signaling events leading to the modulation of cell survival, proliferation, migration, and differentiation [reviewed in (104–107)]. ERBB2 (also known as HER2) receptor is a proto-oncogene frequently amplified and overexpressed in many human cancers. Unlike the other ERBB receptors, ERBB2 is unable to bind ligands but heterodimerizes with other ERBB receptors, stabilizing the ligand interaction with the coupled receptors, enhancing and diversifying the ligand-induced receptor signaling (108) [reviewed in (107)]. Several strategies have been developed to target the key role of ERBB2 signaling in tumor development and progression. Successful approaches are represented by treatment with humanized ERBB2-targeting antibodies (e.g., trastuzumab and pertuzumab) and tyrosine kinase multi-HER inhibitors (e.g., lapatinib, tucatinib, afatinib, neratinib, and dacomitinib), which effectively showed ERBB2 inhibition and tumor regression, particularly in the treatment of mammary carcinomas [reviewed in (109)].

The cardiotoxicity of ERBB2-directed therapeutics is consequent to the inhibition of the signaling activated by Neuregulin-1 (NRG1), a paracrine growth factor released by cardiac endothelial cells featuring pivotal functions in the heart (Figure 5) [reviewed in (110–112)]. NRG1, together with its tyrosine kinase receptors ERBB4, ERBB3, and ERBB2, is essential for heart development (113–115) [reviewed in (110, 116, 117)] and tunes heart regenerative, inflammatory, fibrotic, and metabolic processes (118, 119) [reviewed in (110, 117, 120–122)]. In cardiomyocytes, the most prominently expressed NRG1 receptors are ERBB4 and ERBB2 (123) and NRG1 stimulates fetal/neonatal cardiomyocyte proliferation, hypertrophy, sarcomerogenesis, and survival (114, 115, 124–127) [reviewed in (110, 116, 117, 120, 121)]. ERBB2 forms heterodimers with ERBB4 and is necessary for NRG1-elicited cardiomyocyte proliferation during embryonic and neonatal stages (122, 124). However, cardiac ERBB2 expression levels decline soon after birth in mice, as part of the mechanism leading to cardiomyocyte terminal differentiation, cell cycle withdrawal and loss of cardiac regenerative ability (124) [reviewed in (122)].

Despite low levels described in adulthood, ERBB2 appears to play a role in the prevention of dilated cardiomyopathy. Indeed, mice with ventricular-restricted deletion of ERBB2 exhibited multiple independent parameters of dilated cardiomyopathy, such as chamber dilatation, wall thinning, and decreased contractility (128). Decreased NRG1 signaling in postnatal life is associated with adverse cardiac function and susceptibility to stress [reviewed in (110, 116)]. The expression and activation of ERBB4 and ERBB2 receptors were found lower in myocardium from HF patients (129). In mice subjected to pressure overload, ERBB4 and ERBB2 undergo relevant reduction at mRNA and protein levels with the progression to HF (130).

Conversely, enhanced activity of NRG1 counteracts cardiac remodeling and HF progression [reviewed in (110, 116)]. Systemic administration of NRG1 improves cardiac function following various types of cardiac injuries in adult mice (115, 127, 131, 132) [reviewed in (110, 133)] and HF patients (117, 134–136) [reviewed in (137)].

Cardiac upregulation of ERBB2 was documented upon adverse hemodynamic or other stressful or toxic stimuli, including anthracycline therapies (138, 139). This increase is required to sustain cardiomyocyte survival and cardiac function under stress conditions. Indeed, cardiomyocytes isolated from mice with ventricular-restricted deletion of ERBB2 were more susceptible to anthracycline toxicity, revealing a role for ERBB2 in cardiomyocyte survival upon chemotherapy administration (128). Conversely, cardiac-specific overexpression of ERBB2 in mice has been shown to decrease cardiomyocyte death upon doxorubicin administration (140).

EGFR (also known as ERBB1) is associated with cancer progression and its inhibition via monoclonal antibodies (such as cetuximab and panitumumab) or TKIs (such as erlotinib and gefitinib) has been the first strategy evaluated among growth factor receptors targeting therapies (141, 142). Nowadays, EGFR inhibitors are clinically used for the treatment of several solid cancers, including lung, head and neck, colorectal, and pancreatic cancers (142). Although cetuximab-associated cardiotoxicity has been reported in the clinical literature, the incidence of cardiac events in patients remains very low (143, 144).

In addition to single- or multi-targeted ERBB family inhibitors (see the previous paragraph), other multi-targeted TKIs were developed to effectively block multiple pathways of intracellular signal transduction. The broad kinase-signaling inhibition of several TKIs, such as sunitinib, sorafenib, imatinib, and nilotinib, includes the vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), BCR-ABL, and c-KIT. This wide action results in a strong anti-malignancy effect of this class of drugs, although correlated with reversible myocardial dysfunctions with a wide range of severity (180) [reviewed in (37, 181–183)]. Clinical analysis of TKI anti-tumoral therapies shows that compounds with broader off-target effects as kinases inhibitors (lower selectivity in targeting a specific kinase) correlated to higher degree of cardiotoxicity, particularly in case the inhibited kinase plays a role in the maintenance of the cardiovascular system (184–186) [reviewed in (37)]. In this regard, sunitinib, which targets VEGFR/PDGFR and interferes with more than 30 tyrosine kinases; sorafenib, which targets VEGFR/PDGFR and inhibits at least 15 tyrosine kinases, including RAF/MEK/ERK pathway, and ponatinib, which targets BCR-ABL and several other RTKs, are responsible for major clinical concerns related to cardiotoxicity (172) [reviewed in (37, 187, 188)]. Of note, these three compounds (sunitinib, sorafenib, and sonatinib) target VEGF, PDGFR, and c-Kit, namely three tyrosine kinase receptors involved in multiple key functions in the cardiovascular system, whose inhibition is likely the cause of the observed cardiotoxic effects (Figure 6). Particularly, sunitinib, which presents an effective multi-targeted inhibition of growth-factor receptors able to reduce the angiogenesis and tumor cell survival/proliferation (182, 189), is considered more cardiotoxic than other anti-angiogenic and TKI drugs (182). Based on clinical studies, 47% of patients receiving sunitinib treatment exhibited hypertension, up to 28% showed LV dysfunction, and 8% developed CHF [reviewed in (15)]. Patients with pre-existing cardiovascular diseases or previous cardio-toxicant exposure show even higher risks [reviewed in (190–192)]. However, cardiac dysfunctions induced by sunitinib and other inhibitors of tyrosine kinases have shown high reversibility; after treatment withdrawal, hypertension and cardiac dysfunction were alleviated or wholly restored (193) [reviewed in (37)]. Indeed, the majority of sunitinib-treated patients were able to carry on with sunitinib therapy following the resolution of cardiovascular events (193). Similarly, reversible cardiotoxicity has been reported upon sorafenib treatment [reviewed in (76)].

The cellular and molecular details of the observed elevated blood pressure and cardiac dysfunction in patients treated with anti-VEGF/PDGFR drugs, such as sunitinib and sorafenib, are not fully understood. Nevertheless, sunitinib- and sorafenib-induced VEGFR inhibition was suggested to reduce the production of the vasodilator nitric oxide (NO) by endothelial cells, in turn resulting in hypertension [reviewed in (15, 194)]. Hypertension is known to lead to capillary rarefaction, which may be responsible for the cardiac dysfunction observed in sunitinib and sorafenib-treated patients [reviewed in (15)]. Indeed, given the high energy dependency, the heart is usually highly vulnerable to any altered blood supply. However, the capillary rarefaction potentially responsible for cardiac dysfunction may also be a direct consequence of reduced angiogenesis following sunitinib- or sorafenib-induced VEGFR inhibition [reviewed in (15, 194)]. Further, sunitinib- or sorafenib-induced PDGFR inhibition was suggested to induce the loss of pericytes, in turn leading to coronary microvascular dysfunction (195) [reviewed in (15, 194)]. Sunitinib, as an off-target effect, has also been suggested to inhibit AMPK activity, in turn inducing energy depletion in cardiomyocytes (184). However, another study found that sunitinib treatment in cardiomyocytes does not affect cellular ATP levels and that myocytes are not protected from sunitinib by pre-treatment with AMPK-activating drug metformin (189).

Imatinib, a TKI that inhibits BCR-ABL fusion protein, c-KIT, and PDGFR, is used to treat chronic myeloid leukemia and gastrointestinal stromal cancers. Despite initial fears (196), the rate of cardiotoxicity upon imatinib treatment was shown to be very low, with less than 1% of the patients developing HF [reviewed in (37, 197)]. Nevertheless, the inhibition of CaMKII in adult rat cardiac fibroblasts was shown to reduce the production of mitochondrial superoxide triggered by sunitinib and imatinib treatments (198).

Interestingly, ponatinib, a BCR-ABL kinase inhibitor developed to treat patients with imatinib resistance driven by T315I “gatekeeper” mutation, has been associated with a high rate of cardiovascular adverse events. Indeed, more than 20% of patients receiving ponatinib treatment experienced adverse cardiovascular events, and 5% developed CHF [reviewed in (181, 197)]. Of note, these cardiotoxic effects are often reversible with interruption of the therapy (181). The mechanisms of ponatinib-induced cardiotoxic effects are unclear; however, they were suggested to be consequent to thrombotic microangiopathy and consequent ischemia (Figure 6) (199), although cardiomyocyte death was also reported to occur in the zebrafish model (200).