Antioxidant Protection against Trastuzumab Cardiotoxicity in Breast Cancer: History
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Contributor:
Gabriel Méndez-Valdés
,
Francisca Gómez-Hevia
,
Maria Chiara Bragato
,
José Lillo-Moya
,
Catalina Rojas-Solé
,
Luciano Saso
,
Ramón Rodrigo

Breast cancer is the most frequent malignant neoplastic disease in women, with an estimated 2.3 million cases in 2020 worldwide. Trastuzumab is part of the monoclonal antibodies used as targeted therapy against HER2 receptor, whose major problem is its cardiac safety profile, where it has been associated with cardiotoxicity. The appearance of cardiotoxicity is an indication to stop therapy.

  • antioxidants
  • cardiotoxicity
  • immunotherapy
  • oxidative stress
  • trastuzumab

1. Trastuzumab Therapy in Breast Cancer

Human epidermal growth factor receptor 2 is part of a bigger family of epidermal growth factor receptors that comprises HER1, HER2, HER3, and HER4 [1]. In particular, HER2 is of crucial importance, since its overexpression triggers multiple downstream pathways required for the abnormal proliferation of cancer cells. Typically, HER2 is expressed at a low level on the surface of epithelial cells, and it is necessary for the normal development of many tissues, including those of the breast, ovary, lung, liver, kidney, and central nervous system. In contrast, in breast cancer cells, immunohistochemical analyses have revealed extremely high levels of HER2, which can reach up to two million receptors per cell [2].
Physiologically, HER2 activation happens through a receptor homodimerization or heterodimerization. Its activation then triggers a broad spectrum of downstream cascades to promote numerous outcomes, including cell growth, proliferation, and survival. The phosphorylated tyrosine residues on the intracellular domain activates phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), which drives cell survival. Also, the mammalian homologue of the son of sevenless (SOS) activates via MAPK, driving cellular proliferation. One of the downstream effects is the production of vascular endothelial growth factor (VEGF) supporting angiogenesis [1].
Trastuzumab is a monoclonal antibody against HER2 [3]. It consists of two antigen-specific sites that bind to the juxtamembrane of the extracellular domain of HER2, thus preventing the activation of its intracellular tyrosine kinase receptor [1]. Based on that, the mechanisms of action of TZB can be divided into three main subgroups: HER2 degradation, antibody-dependent cytotoxicity (ADCC), and MAPK and PI3K/AKT interference. While the latter mechanism is the most well-known, the former is still concerning. Indeed, it was observed that the binding of TZB to HER2 recruits tyrosine kinase–ubiquitin ligase c-Cbl to its docking site, where HER2 degradation happens [1].
Regarding the antibody-dependent cytotoxicity mechanisms, it has been demonstrated by Clynes et al. that natural killer cells could target HER2-overexpressing cells coated with TZB via a CD16-mediated ADCC mechanism [4].
Treatment with TZB has shown a lot of benefits in patients with BC in terms of survival, reduced recurrences, metastases rates, and second tumors other than BC [5]. A four-year follow-up randomized controlled trial showed that treatment with adjuvant TZB for 1 year is associated with persisting benefits in women with early HER2+ BC [6]. An 11-year follow-up of TZB after adjuvant chemotherapy in patients with HER2+ early BC showed that 1 year of adjuvant TZB significantly improves long-term disease-free survival, but 2 years of TZB had no additional benefit [7].
Trastuzumab and Cardiotoxicity
Despite the demonstration that TZB improves survival in non-metastatic breast cancer patients, its mechanism of action brings about a series of adverse effects among which cardiotoxicity has been shown to be the most important. This is because TZB also blocks the function of neuregulin, which is required for normal cardiac growth and maintenance [8].
In fact, TZB is crucial in the prognosis of HER2+ subtypes of cancer patients; approximately 3 to 7% of patients receiving this drug as monotherapy have experienced cardiac dysfunction [9]. Trastuzumab is used frequently with anthracyclines, and its cardiotoxicity is not dose-dependent and is usually reversible, unlike anthracycline [8]. However, it has been questioned whether TZB cardiotoxicity is always reversible [10]. In this combination, it has been reported that this adverse effect increases up to 13% in patients using paclitaxel with TZB and 27% if used in combination with an anthracycline [9]. In a Phase 3 clinical trial developed by Slamon et al. [11], patients with HER2+ metastatic breast cancer, 27% of the subjects receiving TZB plus chemotherapy experienced cardiac dysfunction, compared with 8% of patients receiving chemotherapy alone. Gianni et al. in a RCT with treatment with TZB for 1 year after adjuvant chemotherapy reported 87 patients (5%) where TZB was discontinued due to cardiac problems, with 33 patients with symptomatic congestive heart failure and 62 with confirmed significant left ventricular ejection fraction (LVEF) drop [6].
Different interventions have been tested in an attempt to show that non-pharmacological measures such as regular, moderate intensity, supervised exercise could function as a primary prevention measure against heart failure in this group of patients [12]. The most used drugs have been beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists. Among beta-blockers, carvedilol [13] and bisoprolol [14] have been shown to have a protective effect against TZB cardiotoxicity. In the same context, lisinopril [13] and perindopril [14] have been tested, showing a similar effect to previous drugs. These findings could be more beneficial if initiated in the first 6 months post-treatment [15]. On the other hand, candesartan has been shown to have beneficial effects in mitigating LVEF decline [16], but a study by Boekhut et al. [17] found no benefit with this drug. Other interventions tested have been the use of statins, where Calvillo-Argüelles [18] found that this treatment was independently associated with a lower risk of cardiotoxicity, while in a study by Abdel-Qadir et al. [19], no statistical association was found. On the other hand, eplerenone has been tried, which has also been ineffective [20]. Other drugs such as sacubitril/valsartan are currently being tested [21]. The results obtained, and the discrepancies may be due to the different inclusion criteria, endpoints, chemotherapy, and immunotherapy regimens.

2. Potential Role of Antioxidants as Adjunct Therapeutic Agents

As previously mentioned, the relationship between cancer and oxidative stress has been demonstrated via elevated levels of oxidative stress biomarkers and decreased levels of antioxidants in cancer patients [22]. However, the role of oxidative stress is variable between the different types of existing cancer and the signaling pathways involved [23]. In the case of breast cancer, it has been reported that types positive for estrogen receptors present high levels of oxidative stress added to the fact that those triple negative breast cancer would present lower levels of 8-hydroxy-2′deoxyguanosine, thus supporting the role that estrogen receptors such as HER2 could have in the induction of oxidative stress in breast cancer and even indicating a possible differentiation between the various breast cancer subtypes and the role of oxidative stress in each of them [23][24][25][26][27]. In addition, the levels of oxidative stress would be related to the therapy used, where the role of oxidative stress induced by anthracyclines within their mechanism of action has been very well-documented, which entails a high risk of cardiotoxicity in those patients [28]. Trastuzumab as immunotherapy in breast cancer also induces early changes in the levels of biomarkers of oxidative stress and antioxidants, having been reported to have increased malondialdehyde (MDA) levels and decreased SOD activity in patients who received TZB compared to the levels found prior to the treatment. It has also been reported that the decrease in LVEF would correlate negatively with changes in MDA levels and positively with changes in SOD activity [29].

2.1. Nuclear Factor Erythroid-2-Related Factor 2

As previously mentioned, using oxidative stress as a target to lessen cardiotoxicity induced by cancer therapy is plausible, and numerous adjuvant drugs have been tested to attenuate this cardiac damage, where the redox state can be modified by supplementing exogenous antioxidants. In addition, it could resort to the use of drugs that activate endogenous antioxidant response pathways, such as nuclear factor erythroid-2-related factor 2 (Nrf2). However, this last point gives a space for discussion in the literature because of the dual role that the Nrf2, the main regulator of the antioxidant response, could have in the context of cancer. It is considered an indirect antioxidant and is released from its KEAP1 repressor protein when there is an increase in oxidative stimulus under certain ranges, being able to translocate to the nucleus and bind to the endogenous antioxidant response site (ARE), starting transcription of genes encoding for both enzymatic and non-enzymatic antioxidants molecules, such as SOD, CAT, GSH, GPX, GR, among others [23][30][31]. However, in a normal cell context, Nrf2 has a preventive role on carcinogenesis by reducing oxidative stress and promoting gene repair. In addition, the prolonged activation of this transcription factor could be deleterious in the context of cancer cells, since it could finally deliver mechanisms of resistance to therapy, evading cell death and promoting malignancy and cancer metastasis [32].

2.2. Dexrazoxane

Currently, dexrazoxane (iron chelator, acting indirectly as an antioxidant by preventing the formation of hydroxyl radical) is the only medication approved by the United States Food and Drug Administration to prevent anthracycline cardiotoxicity; however, its use is highly restricted to patients with metastatic breast cancer who have received a cumulative dose greater than 300 mg/m2 doxorubicin and need to continue therapy to maintain tumor control [28]. Therefore, there is already previous data for the appropriate use of an antioxidant as adjuvant therapy to attenuate cardiotoxicity induced by cancer therapy.

2.3. Monoclonal Antibodies and N-Acetylcysteine

In the case of specific harm caused by TZB, a preclinical study evaluated the role of oxidative stress in the myocardial damage produced by the blockade of erbB2 receptors through the use of monoclonal antibodies in a culture of rat cardiomyocytes, reporting that the cardiomyocyte death would occur through a ROS-mediated mitochondrial pathway. In turn, the study also demonstrated that the use of N-acetylcysteine ameliorated the damage, so the authors concluded that the regulation of the redox state could be an option to attenuate the cardiotoxicity induced by TZB [33].

2.4. Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFAs) are fatty acids that have more than one double bond between their carbons and this group includes omega-3 and omega-6 fats. Both are essential for human beings since they are not produced endogenously, but we must obtain them from food. PUFAs in recent studies have shown pleiotropic actions on cell function, such as their antioxidant effect, since they are incorporated into the cell membrane and are capable of modifying redox signaling. This is related to the prevention of cardiovascular diseases [34][35], especially with omega-3 due to the reduction of risk factors and hyperlipidemia, inhibition of endothelial dysfunction, inhibition of inflammation, reduction of oxidative stress, antiarrhythmic effects, vasodilation, and reduced blood pressure [36][37]. Moreover, Abdellatif et al. showed that calanus oil (rich in omega 3) has the potential of regulating myocardial remodeling and oxidative stress, resulting in a anti-hypertrophic effect. This study also demonstrated that this PUFA decreased the elevated cardiac enzymes (LDH and CK-MB) and MDA, increased antioxidant status of the heart, and ameliorated the histopathological and structural changes in cardiac tissues and prevented myocardial fibrosis [38].
However, there are debatable outcomes between different studies according to the methodology used and the clinical stage of the disease [39][40]. Regarding the PUFA prevention of cardiotoxicity induced by antitumoral agents such as TZB, there is a lack of information about it, and most of the investigations have been carried out under the conditions of chemotherapy and radiotherapy or adjuvant therapies. Nevertheless, studies showed that PUFA (omega 3) may attenuate the side effects of the therapy and maintain homeostasis and reduce oxidation and its consequent inflammation, which induces accumulation of dysfunctional proteins and DNA damage in muscle as well as preservation of muscle and the increase or maintenance of body weight and improves treatment tolerance [41][42]. In addition, TZB reduces breast tumor growth and enhances the effectiveness of the treatment, reducing HER2 signaling in vitro [43]. Likewise, Ravacci et al. showed that PUFAs modify HER-2 signaling, causing a disrupted lipid raft through decreasing activation of AKT, ERK1/2, and induced apoptosis [44].

2.5. Coenzyme Q10

A study carried out in a culture of human fetal cardiomyocytes demonstrated that the use of coenzyme Q10 increased cell viability and decreased biomarkers of oxidative stress and inflammation [45]. In vivo studies carried out in rats to evaluate cellular response after being subjected to TZB plus antioxidant treatment have also obtained favorable results, reporting increased cell viability or decreased apoptosis in rat cardiomyocytes [46][47][48][49][50].

2.6. Ascorbic Acid

Ascorbic acid or vitamin C is an organic acid with antioxidant properties. Humans and other animals are not capable of synthesizing it endogenously, therefore it must be ingested through food. In one study, high doses of AA (≥10 mM) significantly reduced cell viability of all breast cancer cell lines in combination with conventional antitumor drugs such as TZB, eribulin mesylate, tamoxifen, or fulvestrant [51], and good tolerance and safety have been demonstrated. It has been suggested that the anticancer effect of AA is through H2O2 accumulation due to CAT deficiency in cancer cells and subsequent cell death by apoptosis, pyknosis, and necrosis and through the nuclear translocation of an apoptosis-inducing factor. Therefore, millimolar concentrations of extracellular AA kill cancer cells but not normal cells [52][53]. Although the use of AA in an antitumoral context is still controversial, this is a mainstay of breast cancer treatment when compared to chemotherapy or endocrine therapy alone [51].

2.7. Other Antioxidants Molecules with Antioxidant Effect

Other studies that have also focused on studying mitochondrial dysfunction due to damage by TZB in rat hearts through the use of antioxidants or drugs with antioxidant effects, such as curcumin, chrysin, thymoquinone, melatonin, metformin, α-linolenic acid, flaxseed, and secoisolariciresinol diglucoside have obtained favorable results, improving mitochondrial dysfunction and being associated with an increase in antioxidant enzymes and decreased oxidative stress biomarkers [47][54][55][56].
There is a need to continue carrying out preclinical studies and advancing existing clinical studies that can test antioxidant compounds as pharmacological agents for an adjuvant therapy to prevent cardiotoxicity mediated by oxidative stress induced by TZB.

This entry is adapted from the peer-reviewed paper 10.3390/antiox12020457

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