Introduction: the problem's burden
With recent advances in chemotherapeutic protocols, cancer survival has notably improved,1,2 but cardiovascular disease (CVD) has become a leading cause of morbidity and mortality among cancer survivors.3 There are at least two links between CVD and cancer: first, in most cases, cardiovascular and oncological diseases share the same risk factors, for example, smoking obesity4; second, antineoplastic drugs can produce short- and long-term adverse cardiovascular events. The most common consequence of antineoplastic drug-induced cardiotoxicity (CTX) is an asymptomatic decrease in the left ventricular ejection fraction (LVEF). Other consequences are arrhythmia, hypertension, myocardial ischemia, thromboembolism and heart failure.5 Left ventricular dysfunction caused by anthracyclines (ANTs) has historically been the most relevant form of CTX.6 Nevertheless, new biological drugs may also be cardiotoxic given that they target pathways that play a role in cardiac homeostasis, especially when the heart faces stressful conditions such as hypertension or hypertrophy.2 For instance, human epidermal growth factor receptor 2 (HER2/ErbB2) inhibitors and angiogenesis inhibitors are able to affect cardiac metabolism and contractile proteins.7–10 CTX from these drugs, known as type II left ventricular dysfunction, does not manifest with cardiomyocyte rearrangements and is usually reversible with treatment discontinuation.11 In contrast, ANT-induced CTX, known as type I toxicity, is generally irreversible, with evident ultrastructural myocardial damage.11 Nevertheless, these two forms of toxicity may overlap: for instance, trastuzumab, an anti-ErbB2 antibody, can lead to irreversible myocardial injury in patients who have been previously treated with ANT.12
In this manuscript, we describe mechanisms of left ventricular dysfunction induced by the main antineoplastic agents in order to illustrate the molecular and cellular basis of potential innovative therapeutic routes to preventing CTX induced by such agents.
Key mechanisms of cardiotoxicity by anticancer drugs
ANT-induced CTX is a well-known adverse effect. A recent prospective study13 on 2625 patients treated with ANT over a 4-year follow-up reported a 9% incidence of CTX. The underlying mechanisms have not yet been fully clarified, but myocyte damage has been widely attributed to the production of reactive oxygen species (ROS) with subsequent lipid peroxidation of membranes, vacuolation, irreversible damage and myocyte replacement by fibrosis.14–18 Recent data suggest that ANT-induced CTX is also the result of ANT interaction with topoisomerase II-beta (Top2-beta) in cardiomyocytes.19 In cancer cells, ANT targets the enzyme Top2-alpha, forming the ternary Top2-doxorubicin-DNA cleavage complex, which triggers cell death. In adult mammalian cardiomyocytes, which express only the Top2-beta isoform, doxorubicin also interacts with cardiac Top2-beta, and the Top2-beta-doxorubicin-DNA complex can induce DNA double-strand breaks, which also leads to cell death. Recent murine studies show that cardiomyocyte-specific deletion of the gene Top2-beta protects from the development of progressive heart failure triggered by doxorubicin-induced DNA double-strand breaks in cardiomyocytes.18
Anti-epidermal growth factor receptor drugs
Trastuzumab is a monoclonal antibody that targets ErbB2 (HER2 in humans), which is over-expressed in 25–30% of breast cancers.20 Its CTX ranges from asymptomatic decreases in LVEF to congestive heart failure.2,7,9,21,22
The CTX of anti-ErbB2 drugs has been attributed to their blocking fundamental actions of neuregulin-1 in the heart,23 where it acts via ErbB4/ErbB4 homodimers and ErbB4/ErbB2 heterodimers to stimulate protective pathways in response to stress.23 By blocking neuregulin-1 cardiac effects, ErbB2 inhibitors can render the myocardium more vulnerable to any type of harmful stimuli. Unlike in ANT-induced CTX, the effects of trastuzumab do not appear to be dose-related, and trastuzumab CTX has usually been considered transient and reversible. Nevertheless, ErbB2-inhibiting treatments may trigger irreversible cardiac damage in patients with pre-existing cardiovascular risk factors or CVD, including pre-existing systemic hypertension, obesity and advanced age or left ventricular dysfunction.11
It was found that ErbB2 knockout mice treated with ANT developed dilated cardiomyopathy with a higher prevalence of cardiomyocyte death.24 Accordingly, the combination of trastuzumab with other cardiotoxic agents, mainly ANT, elicits greater CTX25,26 because once the ErbB2 protective mechanisms are blocked, the oxidative damage induced by ANT proceeds without control.11
Emerging data raise concerns about irreversible systolic dysfunction in up to 40% of patients who are treated with trastuzumab after ANT: these observations support the mechanistic concept that trastuzumab may act as a modulator of ANT-related toxicity.12
Anti-angiogenic drugs interfere with vascular endothelial growth factor (VEGF) signalling,2,27,28 which contributes to the integrity of coronary and systemic circulation as well as cancer vascularization; it also modulates cardiomyocyte function.7–9,28–30 Therefore, VEGF blockade may lead to hypertension, thrombo-embolism, left ventricular dysfunction and heart failure.31,32 The antibody bevacizumab interferes only with VEGF binding to the VEGF receptor. The tyrosine kinase inhibitors, sunitinib and sorafenib, may induce cardiovascular toxicity by inhibiting VEGF receptor and other on-target and off-target kinases that are involved in maintaining cardiovascular balance: c-Kit, platelet-derived growth factor receptor alpha and beta, rearranged during transfection, FMS-related tyrosine kinase 3 (FLT3), colony-stimulating factor 1 receptor, and ribosomal S6 kinase, with consequent activation of the intrinsic apoptotic pathway and AMPK (important for the response to energy stress with worsening ATP depletion), Raf-1/B-Raf, c-Kit and FLT3.7,8,28
Hypertension is one of the most common side-effects of VEGF signalling pathway inhibitors. Its incidence ranges from 19 to 47%, and it appears to have a key role in the pathogenesis of subsequent left ventricular dysfunction.33,34 Mechanisms of hypertension include decreased NO signalling, increased endothelin-1 production and capillary rarefaction in the endothelium, which may worsen the ventricular-arterial coupling.35
Antiblastic drug-related cardiotoxicity: strategies for prevention
ANT-induced cardiac side-effects are dose-dependent.36 Patients with no cardiovascular risk factors usually tolerate cumulative doses of doxorubicin of up to 300 mg/m2 (corresponding to 550 mg/m2 of epirubicin) quite well, with an heart failure rate of less than 2%.37 Nevertheless, subclinical myocardial damage can be observed even at low doses, such as 200 mg/m2 of epirubicin.38,39 Above this dosage, the rates of CTX rise exponentially.2 Accordingly, the primary preventive approach is pharmacokinetic, based on reducing lifetime cumulative doses (Table 1). For instance, structural modifications of the basic doxorubicin molecule—such as the most used epirubicin, which has a lower half-life—reduce CTX, as shown in an extensive metanalysis40 (Table 1). In contrast, a significant inter-individual heterogeneity has been observed: patients more than 65 years of age and children, for example, may develop CTX at lower cumulative doses. Risk factors that may increase the likelihood of developing heart failure after ANT include pre-existing CVD, hypertension, increased distance from ANT treatment completion, female sex and genetic pre-disposition.36
Moreover, the modality of ANT administration can influence the CTX entity. In animal models, pharmacokinetic studies demonstrated that although ANT concentrations in tumour tissue were the same with continuous infusion or bolus administration, ANT concentrations in the heart were higher with the bolus, leading to higher clinical CTX.41 Increasing the infusion period clearly reduces CTX without compromising oncological efficacy42 even if an infusion that exceeds 96 h is associated with multiple local and general complications. Continuous doxorubicin infusion for more than 48–72 h has proven effective and is widely used in patients who are affected by sarcoma or lymphoma. Conversely, in children with acute lymphoblastic leukaemia, continuous doxorubicin infusion did not prove to be more cardio-protective than bolus administration.43 Thus, clinical studies supported administration by infusional schedules as a preventive strategy.40,44,45
Pre-clinical studies determined that encapsulating conventional ANT in liposomes reduces the incidence and severity of cumulative dose-related cardiomyopathy, whereas preserving antitumor activity. This pharmacokinetic strategy provides different tissue distribution with equivalent efficacy but lower CTX.46,47 Indeed, liposomal preparations favour the accumulation of the liposomes into the tumour tissue because of increased intra-tumoural capillary permeability and reduced lymphatic drainage.48 In contrast, the uptake of the drug into myocardial tissues is decreased because the heart is supplied by vessels with tight junctions and is well drained by lymphatics.
Another mechanism by which liposomal doxorubicin may reduce CTX is slowing down drug release and blunting the peak plasma levels of the free drugs that are associated with bolus injections of conventional doxorubicin. In addition, pegylated liposomal doxorubicin (PLD), because of the polyethylene-glycol grafting on the liposome bilayer, has lower uptake by the mono-nuclear phagocyte system, resulting in a unique pharmacokinetic pattern with extremely long half-life, slow clearance and small volume of distribution.
A great deal of clinical evidence attests to the excellent therapeutic index of liposomal formulations in the two major areas of ANT application: breast cancer and lymphoma.
Two phase III studies in metastatic breast cancer (MBC),49,50 by comparing non-pegylated liposomal doxorubicin (NPLD) and conventional doxorubicin, showed similar antitumor efficacy in both treatment arms but a significantly lower prevalence of CTX and cardiac events in the NPLD group. Although the median survival time was not different between the two groups, the two indexes of antitumor efficacy (response rate and median time to treatment failure) were higher in the NPLD group. Another phase III study of MBC,51 in comparing PLD and epirubicin, found no difference in overall response rate or overall survival but showed greater efficacy for PLD, whereas CTX was low in both groups with no difference between the two arms. The results of that study are difficult to interpret because the two drugs were not used in equipotent doses. Another phase III study on MBC showed a lower rate of CTX in patients who were treated with PLD than in those who were treated with conventional doxorubicin, with no differences in terms of antitumor efficacy.52
It is well established that although the co-administration of trastuzumab with conventional ANT is highly effective, it also exposes patients to unacceptable risk of CTX. The low propensity of liposomal ANT to cause CTX is documented by studies that evaluated the efficacy and safety of these preparations when they were co-administered with trastuzumab. A prospective randomized phase III study that aimed to compare the efficacy and safety of trastuzumab and paclitaxel with or without NLPD in patients with HER2-over-expressing MBC showed that the frequency of adverse events (severe heart failure or cardiac death) was 3% compared with 1% with NPLD, but there was no significant difference in CTX between treatment arms.
In terms of lymphoma, a number of retrospective or prospective observational studies demonstrated that in patients who are at high risk of CTX because of advanced age, frailty, pre-treatment with ANT, or concomitant CVD, liposomal ANT offers a unique possibility for using ANT. In this real-life patient setting, treatment responses to both PLD and NPLD were comparable with those of conventional treatment regimens.53,54
In conclusion, substituting conventional ANT with their liposomal formulation is an effective strategy for mitigating CTX in MBC and in lymphoma patients who are at high cardiac risk and for whom liposomal ANT may represent the only opportunity to use ANT. There is urgent need, however, for randomized studies with liposomal ANT and longer term follow-up in younger, not frail people with early breast cancer or Hodgkin lymphoma, who are expected to have long survival times and, therefore, are at increased risk of late CTX.
The greatest disadvantage of liposomal doxorubicin is its cost, which is the reason this formulation is not widely used; currently, it is approved by the U.S. Food and Drug Administration for ovarian cancer, acquired immune deficiency syndrome–related Kaposi sarcoma, and multiple myeloma after failure of at least one prior therapy55 (Table 1).
Previous or concurrent treatment with other agents that are known to have cardiotoxic effects (such as alkylating or anti-microtubule chemotherapeutics, monoclonal antibody against HER2/erbB2 and/or mediastinal radiation therapy) might influence development of and recovery from ANT-induced cardiomyopathy.56 In particular, the use of ANT and trastuzumab in combination may pose a specific risk for heart failure development. In a recent retrospective cohort study57 of 12 500 women diagnosed with invasive breast cancer, it was observed that compared with women who did not receive chemotherapy, the risk of incident heart failure after 5 years was significantly increased among women who were treated with ANT alone, and it was even greater (with a hazard ratio that showed a seven-fold increased risk) among women who received ANT plus trastuzumab.25
In summary, the cardiomyopathy associated with ANT and trastuzumab is prevalent and growing, and although a number of patient-related risk factors have been identified, to date, no validated clinical prediction tool for identifying high-risk patients before anticancer treatment is available yet. It may be assumed that any insult that has previously damaged the heart or any factor that makes the heart more susceptible to future damage should be considered a potential risk factor for CTX.
Dexrazoxane, a pro-drug that must be infused within 30 min before the intravenous injection of ANT, is the only cardio-protective agent that is currently approved by the FDA for ANT-induced CTX. It is an iron-chelating molecule that, once it enters the cardiomyocyte and is rapidly turned into its active form, counteracts the formation of ANT-iron complexes and the subsequent formation of ROS.58 Its efficacy has been tested in multiple randomized trials and two pooled analyses.59,60 Moreover, the efficacy of dexrazoxane in preventing CTX has been demonstrated in different subsets of cancer patients, not only in women with breast cancer,61 but also in children with acute lymphocytic leukaemia.62
Although it seems that additional mechanisms are responsible for the beneficial effects of dexrazoxane, given that no other iron chelators have demonstrated any cardio-protective effects.58 Indeed, basic science studies have shown that dexrazoxane modifies Top2beta's configuration, preventing its interaction with ANT and thereby inhibiting the formation of Top-DNA cleavage complexes19 (Table 1).
Despite its qualities, dexrazoxane is a largely underused resource. This was initially because of the belief that dexrazoxane may interfere with the antitumor activity of ANT, and it took many years to realize that this was a groundless concern. It is worth highlighting that this belief was generated by a single study61 that showed that dexrazoxane reduced the tumour response rate. It happened that the tumour response rate in dexrazoxane patients was in keeping with what would have been expected based on prior studies with doxorubicin, but the response rate in the placebo group was markedly higher than was expected. It was therefore considered more appropriate to interpret the response rate in that study as anomalous. In addition, it was noted that neither the aforementioned study nor any of the many other randomized controlled studies62,63 has demonstrated that dexrazoxane actually reduces progression-free or overall survival, which are the key endpoints for cancer studies.
When oncologists became less concerned about dexrazoxane, two studies were published that suggested a dexrazoxane-induced risk of a second tumour.64 This association was questioned because of the statistical method that was applied in the first study and because the association did not reach statistical significance in the second study. Finally, the hypothesis that dexrazoxane may enhance the risk of a second malignancy was not confirmed in clinical studies that examined more than 1000 paediatric patients during an extended follow-up.65,66
Although in spite of the strong evidence that indicates cardioprotection, dexrazoxane has been used in recent years with gradually lower frequency.
Another promising cardio-protective strategy is the use of drugs with well known cardio-protective effects. To date, limited data support the use of cardio-protective therapies to prevent or reverse CTX, and this is an actual and challenging issue.
The role of the adrenergic system and beta-blockers
Chronic activation of the sympathetic nervous system plays an important role in the pathogenesis of heart failure.67 According to current European and American guidelines, β-blockers should be used in all patients with reduced LVEF to prevent heart failure hospitalization and mortality,68 but there are still no strong evidence-based recommendations for this therapeutic approach in patients who develop asymptomatic left ventricular dysfunction after anticancer treatments.69
Experimental models showed that β-adrenergic receptor signalling alterations are present in ANT-induced cardiomyopathy just as they are in other forms of dilated cardiomyopathy.70 Cardiomyocytes that were isolated from β2-adrenergic receptor–deficient mice showed significantly increased apoptosis and decreased viability when exposed to doxorubicin.71 The additional deletion of β1-adrenergic receptor rescued these alterations completely. These data suggest a different role of β-adrenergic receptor subtypes in the pathogenesis of CTX with a possible cardio-protective role of β2-adrenergic receptor activation. Thus, a β1-selective antagonist rather than a non-selective β-blocker might offer greater protection against ANT-induced cardiomyopathy, but the net effect of β1 vs. β2 blockage in preventing cancer-related CTX remains to be elucidated. A number of animal studies have shown the beneficial effects of β-adrenergic receptor blockage in terms of mitigating oxidative stress, enhancing lusitropy by preventing myocardial calcium overload72,73 and preserving epidermal growth factor signalling by promoting beta-arrestin signaling74,75 (Table 1).
Some experimental studies suggest that the cardio-protective effects of new-generation β-blockers could be more related to their antioxidant properties than to their β-adrenergic receptor-blocking action. Matsui and co-workers first evaluated the protective effects of carvedilol, a non-selective β- and α1-adrenergic receptor antagonist with strong antioxidant properties, in an animal model of doxorubicin-induced cardiomyopathy.76 They also compared carvedilol and atenolol, a β-blocker without antioxidant properties, and showed that carvedilol prevents doxorubicin-induced cardiomyopathy to a greater extent and with action that is likely related to its antioxidant and lipid-lowering effects.76 Carvedilol was able to prevent doxorubicin-induced ROS release and apoptosis in cardiomyocytes,77 mitochondrial respiration alterations and changes in mitochondrial calcium-loading properties.78
Nebivolol is a third-generation cardio-selective β-blocker with mild vasodilating properties attributed to its interaction with the L-arginine/NO pathway. In a rat model of ANT-mediated CTX, treatment with nebivolol, and to a lesser degree with carvedilol, showed prominent reduction in oxidative stress with greater improvement in left ventricular function correlated with increased NO levels.79,80
In a recent retrospective survey on the incidence of new symptomatic heart failure in patients with breast cancer treated with ANT, trastuzumab or both between 2005 and 2010,81 patients on continuous β-blocker treatment during their cancer treatment were compared with those who were not on a β-blocker. The study showed a significant reduction in the incidence of heart failure in the first group, providing support for the hypothesis that β-adrenergic receptor blockage may be cardio-protective during antiblastic therapies.
Clinical and subclinical doxorubicin-induced CTX were investigated in lymphoma patients after concomitant prophylactic therapy with the β1-selective antagonist, metoprolol, or enalapril vs. no concomitant treatment.82 The incidence of symptomatic heart failure was lower in patients treated with either metoprolol or enalapril, but the difference between the two treatments was not significant. The possible cardio-protective effect of treatment with metoprolol in patients who receive ANT and/or trastuzumab for breast cancer is currently being evaluated in two randomized clinical trials (NCT01434134 and NCT00806390).
The cardio-protective effect of prophylactic use of carvedilol in patients who are undergoing ANT chemotherapy was evaluated in a randomized placebo-controlled clinical trial.83 At the end of a 6-month follow-up, the mean LVEF in the carvedilol group was similar to the baseline ejection fraction, but it was significantly decreased in the control group; diastolic dysfunction also occurred less often in the carvedilol group. Although the major limitations of these studies were small sample sizes and short-term follow-ups; thus, ‘strong’ clinical evidence of the cardio-protective effect of carvedilol is still lacking. To further investigate this aspect, another study is on-going that is evaluating the effects of concomitant carvedilol and lisinopril vs. placebo on LVEF at 52 weeks in 468 women breast cancer (NCT01009918).
The prophylactic use of nebivolol to prevent ANT-induced CTX was recently evaluated in a small randomized placebo-controlled study. Forty-five breast cancer patients were randomly assigned to receive 5 mg/die of nebivolol or placebo. The results at 6-month follow-up showed that left ventricular dimensions and ejection fraction did not significantly change in the nebivolol group but they worsened in patients who were treated with the placebo.84
In summary, the cellular mechanisms by which β-blockers may confer cardioprotection are still largely unknown, and different β-blockers are not equally effective in preventing chemotherapy-induced CTX; moreover, to date, no clinical trials are available that have sufficiently large numbers of patients. It is also important to note that the use of β-blockers may not be easy or free from side-effects in patients who are being treated with active chemotherapeutic agents.
Finally, it is still unclear whether the optimal strategy is to treat all patients or only those who are at high risk for CTX, even in the absence of a reliable method for selecting these patients.
β-blockers could also prevent trastuzumab-related CTX by promoting pro-survival ERK signalling after ErbB2 inhibition74 (Table 1). These drugs are the subjects of other on-going clinical trials (es. MANTICORE-101). The SAFE study is evaluating the effects of the association between bisoprolol and ramipril, and the results of these trials will allow for establishing the role of cardio-protective drugs in trastuzumab-induced CTX.
The role of renin-angiotensin-aldosterone system: angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers
Among the potential mechanisms and multiple determinants of chemotherapy-induced CTX, a key role is played by the activation of the renin-angiotensin-aldosterone system. For a number of years, in fact, an increase was noted in plasma renin activity following administration of ANT.85
A large body of evidence has clarified the role of angiotensin 1 in determining the development of myocardial hypertrophy and left ventricular remodelling after myocardial infarction86 although angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) have been demonstrated to slow the progression of left ventricular dysfunction and prevent heart failure in asymptomatic high-risk patients.87 Patients treated with ANT must be considered at high risk for developing heart failure, and as such, a strong rationale for using drugs with cardio-protective effects in this context is conceivable.
A number of basic science studies have demonstrated the efficacy of ACE-I in ANT-induced CTX.88,89 The main mechanisms that may lead to these beneficial effects are attenuated oxidative stress, reduced interstitial fibrosis, and improved intracellular calcium handling, cardiomyocyte metabolism and mitochondrial function88,89 (Table 1). doxorubicin (DOX) induced a loss of myofibrils, increased apoptosis and significantly impaired heart function in controls, but not in angiotensin 1-knockout mice or in animals treated with ARBs.90 Direct CTX mediated by angiotensin 1 receptor includes stimulating NADPH oxidase, involvement in the genesis of oxidative stress, and activation of mitogen-activated protein kinase, which is responsible for cell growth, inflammation, hypertrophy and apoptosis.89 In addition, ACE-I and ARBs seem to exert cytostatic effects through mechanisms that are still not fully clear. It was found that ARBs suppress signal transduction pathways mediated by growth factors, such as EGF, through the angiotensin 1 receptor's inibition.91 AII-blockers also counteract the angiotensin 2-mediated neovascularization through inducing imbalance in the production and in the function of angiotensin 1 and angiotensin 2, thus increasing angiotensin 2 activity and resulting in apoptosis of cancer cells.92
The prophylactic administration of captopril, enalapril and lisinopril has proven to be cardio-protective in animal models of acute and chronic DOX-induced cardiomyopathy.88 Candesartan was the first ARB that was investigated for its cardio-protective effects in a mouse model treated with daunorubicin.93 More recently, the protective role of telmisartan against the acute CTX induced by DOX has been highlighted.94,95 Telmisartan may be considered the only ARB modulator of peroxisome proliferator-activated receptor-γ, and therefore, it can affect the bioavailability of NO, inhibit the production of inflammatory molecules, such as tumour necrosis factor and interleukin-6, and exert antioxidant and anti-proliferative cells in vessel walls.96
Although administration of ACE-Is or ARBs is associated with reduced morbidity and mortality in human heart failure,97 the potential benefits of renin-angiotensin-aldosterone system inhibition in preventing chemotherapy-induced CTX is under evaluation in on-going randomized trials. To date, the sample sizes in all of the studies that aimed to evaluate the efficacy of the preventive use of ACE-Is or ARBs in patients treated with ANT have been rather small, although clinical results so far suggest a certain protective benefit for their use against ANT-related CTX.
In a study of 114 patients with high troponin I levels within 72 h after ANT administration, after 1 year of treatment, enalapril had significantly reduced the incidence of left ventricular dysfunction in comparison with the placebo.98 Valsartan showed a cardio-protective effect that favoured reduced BNP and left ventricular volumes in patients treated with high doses of ANT.99 In a small prospective study of patients who were treated with epirubicin, telmisartan proved to antagonize the cardiotoxic effects by increasing defences against oxidative stress and preserving myocardial function during treatment100 through 18 months of follow-up.101
Data collected so far on the prophylactic administration of ACE-Is and ARBs in patients on ANT therapy were reviewed in a recent meta-analysis in which the treatment result was associated with a reduced relative risk of developing CTX compared with the placebo.102
Other studies are evaluating the efficacy of combination therapy with ACE-I/ARB and β-blockers in preventing CTX. The OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) sought to evaluate the efficacy of enalapril and carvedilol in preventing chemotherapy-induced left ventricular systolic dysfunction in patients with haematological diseases. The study demonstrated that this combination therapy may be beneficial in ANT CTX, as a less significant reduction in left ventricular function and a lower incidence of heart failure were observed in treated patients compared with the placebo.103 The PRADA (PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy), a randomized, placebo-controlled trial, is currently evaluating the efficacy of candesartan and metoprolol, alone and in combination, in preventing left ventricular dysfunction after ANT treatment. Interestingly, a very recent experimental paper provides novel molecular hints for the use of beta-blockers in the setting of anti-ErbB2 treatments.104
On-going clinical trials are evaluating the role of ACE inhibitors and ARBs as cardio-preventive agents (with lisinopril, NCT01009918 or candesartan, NCT00459771) that might act by decreasing angiotensin-induced blockage of the neuregulin-1/ErbB pathway (Table 1).
Recent recommendations for managing hypertension with anti-angiogenic drugs have been published.34,105 The most commonly prescribed antihypertensive agents are ACE-I and ARBs, β-blockers, dihydropyridine calcium channel blockers and diuretics. Because of the pharmacokinetic interaction of sorafenib and sunitinib with CYP3A4, non-dihydropyridine calcium channel blockers are contraindicated. Considering the other mechanisms that underlie sunitinib-induced CTX, that is, the disrupted mitochondrial function and impaired myocyte energy homeostasis,106 the use of drugs with already demonstrated efficacy in terms of improving myocardial energetics, such as ACE-I and β-blockers107,108 could be an effective cardio-protective strategy (Table 1). Nevertheless, to date, no clinical study has demonstrated the role of these drugs in preventing sunitinib-induced CTX.
Novel horizons in treating cancer-drug-induced cardiotoxicity
Among cardiovascular drugs that are not currently used for treating ANT CTX, HMG-CoA reductase inhibitors (statins) have proven to be potentially effective through a pharmacodynamic mechanism in addition to their pleiotropic antioxidant and anti-inflammatory properties. In experimental studies, lovastatin counteracted doxorubicin-induced cardiomyocyte death by inhibiting Top-beta2-mediated DNA damage109–111 (Table 1). Small randomized clinical trials evaluated the effects of statins in patients who were treated with ANT112,113 and found minor positive results, which need to be confirmed in larger studies.
Late INa inhibition with ranolazine has been proposed as a therapeutic strategy in a number of experimental models of cardiac dysfunction.80,114 Recent work has also highlighted the possible role of ranolazine in counteracting ANT-induced cardiac dysfunction115 (Table 1). In particular, better heart function was observed in mice treated with ranolazine+doxorubicin in comparison with doxorubicin alone, whereas HL-1 cells showed that doxorubicin toxicity with ranolazine was attenuated with reduced oxidative stress. Indeed, doxorubicin in the heart produces imbalances in both Ca2+ and Na+ homeostasis, a characteristic of failing myocytes.116 Enhanced [Na+]i would also be responsible for ROS formation by reducing mitochondrial Ca2+ uptake.117,118 ROS could then stimulate Ca2+/calmodulin kinase II,119 which would interact with the Na+ channel, enhancing late INa and [Na]i120,121 and establishing a vicious cycle of increased [Na+]i and ROS levels.117 The result is a greater exchange of intracellular Na+ for extracellular Ca2+ through the sarcolemmal Na/Ca exchanger, that together with ROS inhibition of SERCA2a and stimulation of RyR2 brings to Ca2+ overload, with electrical and mechanical dysfunction.122 Hence, inhibiting elevated [Na+]i with ranolazine would prevent the occurrence of oxidative damage by reducing ROS generation, offering an advantage over conventional antioxidant strategies that quench ROS after their production. Additional studies will establish whether ranolazine might be used as a therapeutic against ANT-induced CTX. Of note is the INTERACT study,123 which was designed to assess whether ranolazine could relieve ANT-induced diastolic dysfunction, confirming that ranolazine may be a promising cardio-oncologic drug.
Other drugs that may attenuate or prevent ANT-induced cardiac damage are phosphodiesterase-5 inhibitors. It is already known that sildenafil induces cardioprotection against ischemia and reperfusion injury by opening mitochondrial KATP channels, attenuating cardiomyocyte apoptosis, preserving mitochondrial membrane potential and myofibrillar integrity and preventing doxorubicin-induced left ventricular dysfunction.124 Interestingly, tadalafil demonstrated a significant effect in attenuating doxorubicin-induced cardiomyopathy through NO-mediated increases in cGMP levels.125,126
Among other mechanisms involved in ANT-induced CTX, recent advances have highlighted the role of impaired myocardial energetics, expressed by a reduced phosphocreatine/ATP ratio, which precedes left ventricular dysfunction.127 Indeed, ANT interacts with the enzyme creatine kinase, through oxidation of sulphydryl groups of creatine kinase, determining attenuation of its function and subsequent reduced myocardial energetics127 and development of cardiac damage. Further characterization of this interesting mechanism could provide a target for additional preventive treatment. Over-expression of myofibrillar creatine kinase in mice with heart failure because of thoracic aortic constriction significantly increased contractile function,128 suggesting an important role for creatine kinase in heart failure prevention and treatment. Additionally, a recent study demonstrated that creatine kinase over-expression also improves myocardial energetics, contractile dysfunction and survival in a murine model of doxorubicin-induced CTX.129 This evidence offers an appealing new strategy for limiting ANT-related CTX.
Experimental studies have highlighted that sunitinib inhibits AMPK activity and that its restoration reduces cell death.130 These observations led to the hypothesis that promoting AMPK activity with metformin may prevent sunitinib-induced CTX. Although metformin could prevent left ventricular dysfunction in different animal models of cardiac injury131,132 (Table 1), an in-vitro study that focused on sunitinib-related CTX did not demonstrate any beneficial effect of metformin. Interestingly, a recent work133 showed that a TrkB, a tyrosine kinase receptor, and its endogenous ligand brain-derived neurotrophic factor could directly regulate the cardiac excitation–contraction coupling process, independently and in parallel with G protein-coupled receptor (GPCR)-mediated signalling. This supports the concept that tyrosine kinase antagonism during anticancer therapies can disrupt important signalling, consequently impairing left ventricular contractile work and ultimately leading to heart failure.106 At the same time, this work emphasizes the role of tyrosine kinase stimulation by brain-derived neurotrophic factor as an alternative potential therapeutic tool in treating left ventricular dysfunction.
Nutritional supplementation and exercise training
The ROS production generated by ANT can be prevented or mitigated by increasing the levels of endogenous antioxidants or introducing exogenous antioxidants through food supplements. The cardio-protective effect of antioxidants, however, was primarily evaluated in animal models134–136 (Table 1), and although preliminary data suggest that these agents may actually have cardio-protective effects, their clinical utility in preventing CTX requires further study and confirmation.
Non-pharmacologic strategies aimed at countering doxorubicin CTX include lifestyle interventions and exercise ‘pre-habilitation’, a type of preventive exercise rehabilitation. The mechanisms advocate explaining that the positive effects of aerobic exercise include reduced ROS production, negative modulation of pro-apoptotic signalling, improved calcium handling and activation of the AMP-kinase (AMPK) pathway, with ameliorated myocardial energetics137 (Table 1). Moreover, exercise can favourably improve a number of cardiovascular risk factors, including hypertension, high cholesterol and lipids, overweight and obesity, and high blood glucose or diabetes.138 In cancer survivors, a short period of mixed aerobic and resistance exercise improves tolerance and flexibility in physical activity.139
Although a number of studies have tested the role of aerobic exercise in preventing doxorubicin-137 and trastuzumab-related140 CTX and obtained positive results, we need more information to define in greater detail the effects of training as a means of preventing cancer-therapy-induced CTX.141
Conclusion and future perspectives
CTX because of antineoplastic drugs is becoming a determinant of overall prognosis and survival, influencing the quality of life of oncological patients. Cardio-oncology seems to be a field in rapid development.
Before starting any treatment with a chemotherapeutic agent that is burdened with a known or suspected potential to induce CTX, primary prevention to correct pre-existing cardiovascular risk factors or comorbidities is mandatory. Indeed, systemic hypertension, metabolic disorders, arrhythmias and systolic dysfunction, and adverse lifestyle habits, such as smoking, overweight, and lack of physical activity have long been known to increase the risk of CTX in patients who are scheduled to receive ANT.17
The use of primary prevention treatments has not been widely validated yet, and additional investigations that evaluate prevention strategies, such as the use of ACE-I, ARBs and β-blockers in larger randomized trials and in different chemotherapy settings, would be helpful for guiding patient management.142 There will be a greater need for collaboration between cardiologists and oncologists in order to provide optimal contemporary cancer treatments that prevent adverse cardiovascular events. First of all, patients who are at increased risk for heart failure associated with cancer treatments will have to be detected.
With cancer therapies, the main mechanisms of cardiac dysfunction consist of the development of oxidative stress15,17,18,22,39,80,143 and the inhibition of cancer cell signalling pathways that unfortunately also play an important role for the survival and homeostasis of the cardiovascular system.7–9,28
By studying side-effects because of novel antineoplastic drugs, some cardiovascular signalling pathways will be more clearly assessed, with positive consequences for treatment and survival, life expectancy and quality of life for cardio-oncologic patients.144 In the coming years, it is likely that we will be facing a great increase in the market in the number of novel cancer therapeutics that will generate new forms of heart dysfunction8 given that approximately 20% of all of the investments on drug research are currently dedicated to small-molecule kinase inhibitors, the majority of which (approximately 80%) in cancer are small components of inflammatory and other diseases.8 Research on this class of drugs is very lucrative; it is second only to research on compounds that target G protein-coupled receptors, and it does not seem to slow down, with a very large number of kinase inhibitors currently in phase 1 or later clinical trials (approximately 150).8 Concomitantly with these increases in new compounds, researchers will continue to pursue new approaches to CTX that will require novel therapeutic strategies, genetic manipulations, miRNAs, gene transfer etc.80,125,145–152
Future perspectives could include stem cell-based strategies for the prevention of chemotherapy-related CTX. Finally, an interesting and promising approach would consist of separating out subjects with genetic susceptibility to ANT-induced CTX. Following the experimental data on top2beta,18 peripheral blood leukocyte top2beta has been proposed as a surrogate marker of individual susceptibility to ANT-related CTX,152 suggesting that Top2b levels might be useful for stratifying patients according to their individual risk.152–155
Conflicts of interest
There are no conflicts of interest.
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