Statins to Prevent Anthracyclines-Induced Cardiotoxicity

Review Article

Austin Cardio. 2023; 8(1): 1037.

Statins to Prevent Anthracyclines-Induced Cardiotoxicity

Yitong Ma*; Qianru Yuan; Aibibanmu Aizeze; Baozhu Wang

Heart Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, China

*Corresponding author:Yitong MA Heart Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, China. Email: myt-xj@163.com

Received: March 03, 2023 Accepted: April 17, 2023 Published: April 24, 2023

Abstract

While anthracyclines are a class of chemotherapeutic agents that have improved the treatment of a broad spectrum of malignancies, it is one of the most cardiotoxic agents used to treat the tumor. Despite their dose-dependent cardiotoxicity, anthracyclines-based chemotherapy has become the main stay of tumor therapy due to its efficacy. Meanwhile, Statins, widely used in the clinical setting to reduce serum cholesterol levels and to reduce cardiac morbidity and mortality, have pleiotropic biological effects independent of their lipid-lowering effects. Many studies at home and abroad believe that statins can prevent the cardiotoxicity caused by anthracyclines and propose that statins can play beneficial pleiotropic cardiovascular effects through anti-inflammatory and antioxidant mechanisms, thus playing a cardioprotective effect. Illuminating the mechanisms of Anthracyclines-induced cardiotoxicity and Statins associated therapeutic continue to be the main focus in the field of anti-tumor. Therefore, we summarized the current research surrounding the mechanisms of anthracyclines-induced cardiotoxicity and the protective effect of statins on anthracyclines-induced cardiotoxicity and its possible mechanism.

Keywords: Statins; Anthracyclines; Cardiotoxicity; Mechanism; Anti-tumor

Introduction

Anthracyclines such as Doxorubicin (DOX), daunorubicin, idarubicin and so on are a family of potent chemotherapeutics that are broadly used to treat solid tumors (ovary, breast, stomach, brain, and gastrointestinal tumors) and hematological malignancies (lymphoma and pediatric leukemia) [1,2], Anthracyclines can be used alone or combined with other antitumor regimens, such as radiation therapy or monoclonal antibodies [3,4]. However, cardiotoxicity arise as a leading cause of morbidity and mortality among tumor survivors receiving anthracyclines therapy, largely limiting the clinical application of these drugs [5]. Anthracyclines-induced cardiotoxicity involves direct effects of the chemotherapeutics on cardiovascular function and structure, or may be due to accelerated development of cardiovascular diseases. The risk of cardiomyopathy is more than 30% at a cumulative dose of DOX of 400mg/m² and more than 50% at a cumulative dose of 500mg/m² [6]. Even at lower cumulative doses of 240mg/m2, cardiomyopathy can occur in 10–15% of patients and clinical HF (HF) in more than 5% [6]. Anthracyclines-induced cardiotoxicity proves an unresolved major problem in related antitumor therapy, which side effect of inducing cardiac dysfunction has hampered their clinical use. And the mechanism underlying anthracyclines cardiotoxicityremains obscure, increasing evidence points to Anthracyclines-induced Reactive Oxygen Species (ROS), mitochondria damage, Ca2+ overload and iron ferroptosis, cell autophagy and disruption of cardiac metabolism as major targets of anthracyclines--induced cardiotoxicity.

Anthracyclines-Induced Cardiotoxicity

Clinical manifestations of anthracyclines-induced cardiotoxicity: Anthracyclines-induced cardiotoxicity was unrecognized until 1967 when Karnofsky first observed that anthracyclines were associated with chronic Heart Failure (HF) [7]. According to the time of onset, anthracyclines-induced cardiotoxicity presents acutely, early and lately. Acute cardiotoxicity, predominantly supraventricular arrhythmia, transient LV dysfunction and Electrocardiographic (ECG) changes, develops in <1% of patients instantly after infusion and proves usually reversible. However, acute cardiac dysfunction may also evolve into early or late cardiotoxicity [5]. Three distinct types of Anthracyclines-induced cardiotoxicities have been recognized: 1) “acute”, occurring after a single dose or course, within two weeks from the end of treatment; 2) “early onset chronic”, developing within 1 year, is the most frequent and clinically relevant form of cardiotoxicity, usually presenting as a dilated and hypokinetic cardiomyopathy leading to HF; 3) “late onset chronic” developing years, or even decades, after the end of chemotherapy [8]. In the Childhood Cancer Survivor Study, a study of 14358 5-year survivors of childhood malignancies, use of <250mg/m² of anthracyclines were associated with a 2.4-fold higher risk of developing congestive HF compared to those patients who did not receive anthracyclines. This risk increased to 5.2-fold with the use of ≥250mg/m² of DOX [9]. Patients treated with commonly used anthracyclines doses and >65 years old, the rate of Anthracyclines-induced HF even be as high as 10% [10]. Cardinale conducted a prospective study involving 2625 patients with a mean follow-up of 5.2 years that demonstrated a 9% overall incidence of cardiotoxicity with anthracyclines treatment and 98% of patients occurred within the first year and were asymptomatic [11]. In a retrospective study of 640 patients on DOX, which defined cardiotoxicity as Left Ventricular Ejection Fraction (LVEF) <50% with a decrease in >10 absolute points. 32 patients (5%) developed chronic HF. Of those, 38% had mild HF (New York Heart Association (NYHA) Class I or II), 34% developed moderate HF (NYHA Class III) and 28% experienced severe HF (NYHA Class IV) [10]. It is now well established that anthracyclines induced-cardiotoxicity is dose dependent. One large study demonstrated that left ventricular dysfunction (defined as reduction in ejection fraction of >10% below normal) occurred in 10%, 16%, 32%, and 65% at cumulative DOX doses of 250, 300, 400, and 550mg/m² respectively [12]. Thus, even at the lowest dose, anthracyclines can also result in significant left ventricular dysfunction. Risk factors for Anthracyclines-induced cardiotoxicity include lifetime cumulative dose, infusion regimen and any condition that increases cardiac susceptibility, such as pre-existing cardiovascular disease, hypertension, concomitant use of other chemotherapies or mediastinal radiation therapy and older age (>65 years) [13]. Therefore, early detection of cardiac dysfunction is crucial to prevent anthracyclines-induced cardiotoxicity. If anthracyclines-induced cardiac dysfunction is identified early and interfered with HF medications, patients recover easily. In contrast, HF is difficult to treat if detected late after anthracyclines therapy [14].

Mechanisms of anthracyclines-induced cardiotoxicity: The mechanism of anthracyclines-induced cardiotoxicity is not yet clearly. There exist many hypotheses about the mechanism of anthracyclines-induced cardiotoxicity, including oxidative stress hypothesis, cell energy metabolism theory, Ca2+ overload theory, apoptosis theory, immune response theory and so on. The two main accepted hypotheses are as follows and not mutually exclusive: (1) Oxidative stress, which in the presence of iron, generates reactive oxygen species that cause lipid peroxidation of the cell membrane leading to damage of the cardiomyocytes [1,15,16]. (2) Inhibition of topoisomerase 2β, which is active in quiescent non-proliferating cardiomyocytes, can result in the activation of cell death pathways and inhibition of mitochondrial biogenesis [15,16].

Oxidative Stress Hypothesis

Studies showed that oxidative and nitrifying stresses are the key to the anthracyclines induced-cardiotoxicity, which can lead to the oxidation of macromolecules such as lipids, nucleic acids and proteins and disrupt cell function. Anthracyclines can form semiquinone free radicals by losing electrons, and the lost electrons always combine with oxygen to form superoxide radicals, which disproportionately or spontaneously form H2O2. Under the catalysis of superoxide dismutase, H2O2 and superoxide radicals can produce the hydroxyl radicals (OH-), more reactive and toxic. Semiquinone radicals can mediate ROS increase by inhibiting the oxidative cycle of respiratory chain complex I on the mitochondrial inner membrane and gain electrons from NADH or NADPH to form anthracyclines again. Under iron catalysis, a small dose of anthracyclines rapidly generates a large amount of ROS through this cycle to promote lipid peroxidation, resulting in more toxic and stable aldehydes. These aldehydes diffuse and destroy intracellular macromolecules easily [17,18]. Lipid peroxidation usually initiates the arachidonic acid pathway through activation of phospholipase A2 to induce inflammation and apoptosis in vascular endothelial cells. For cardiomyocytes lacking antioxidant enzymes, their antioxidant activity is weaker than other tissue cells. Anthracyclines can significantly reduce the levels of antioxidant enzymes such as superoxide dismutase and catalase, increase the accumulation of reactive oxygen species and further aggravate oxidative stress. Most of the negatively charged cardiolipin exists in the mitochondrial inner membrane and myocardium, which is easy to combine with positively charged anthracyclines to form a stable complex leading to the uncoupling of the respiratory chain and affecting the process of oxidative phosphorylation [1,19]. Cardiomyoblast treated with DOX shows an increased level of NADPH oxidase (NOX) and flavin-containing enzymes such as P450 reductase, nitric oxide synthase leading to increased level of reactive oxygen species and subsequently oxidative stress [20]. In addition to reactive oxygen species, reactive nitrogen as well as plays a key role in the cardiotoxicity caused by DOX. The mechanism may be an increased expression of cardiomyocyte induced nitric oxide synthase and the superoxide ions formed in the DOX redox cycle quickly combine with nitric oxide to produce a powerful oxidant peroxynitrite, which further activates matrix metalloproteinase, causing extracellular matrix remodeling, fibroblast proliferation and collagen deposition, leading to myocardial tissue damage [21]. In addition, anthracyclines can not only increase intracellular iron by activating iron regulatory protein, but also chelate iron ions and trigger the generation of oxygen free radicals, especially hydroxyl free radicals, causing lipid peroxidation of cardiomyocyte membrane and damage of myocardial mitochondrial DNA damage [22].

Inhibition of Topoisomerase 2β

Human DNA topoisomerases are classified into two classes based on structure and mechanisms. Topoisomerase 1 catalyze the formation of DNA single-strand breaks during the catalytic cycle, whereas Topoisomerase2 (Top2) introduce Double-Strand Breaks (DSBs) in the DNA template [23]. The target of anthracyclines action is Top2 which has two isoform, Top 2α and Top 2β. The former exists in rapidly dividing cells such as cancer cells and can combine with anthracyclines to form a lytic complex inducing tumor cell apoptosis. It is considered to be the molecular basis of anti tumor activity. The latter mainly exists in human cardiomyocytes and combines with anthracyclines to form a cleavage complex [24]. On the one hand, this cleavage complex can lead to DNA damage, protein synthesis disorder and specific gene transcription barrier in cardiomyocytes. On the other hand, it presents a strong apoptotic stimulus to activate the P53 apoptosis signaling pathway-dependent mitochondrial dysfunction. It affects oxidative phosphorylation and mitochondrial biosynthesis in cardiomyocytes, causing cardiomyocyte apoptosis and leads to HF [25]. In a mouse model of cardiomyocyte-specific deletion of Top2β gene, the lack of Top2β in heart cells was shown to protect mice from DOX-induced heart cell damage and development of progressive HF [15]. Similar genotoxic mechanisms as well as occur in mitochondrial DNA [17]. Anthracyclines can induce mitochondrial damage because of uncoupling of the electron transport chain, disruption of mitochondrial membrane potential and production of ROS, especially in combination with the disruption of mitochondrial iron metabolism [26]. Cardiomyocytes are rich in mitochondria, which further aggravates anthracyclines-induced cardiotoxicity. Indeed, animal studies demonstrated that chronic Anthracyclines-induced HF relates with imbalances in mitochondrial mass and reduced expression of genes regulating mitochondrial homeostasis [27,28]. But whether TOP2-dependent DSBs in mtDNA or TOP2-independent oxidative mtDNA base lesions cause depletion of mtDNA content is hard to discriminate [29].

Ca2+ Overload and Iron Metabolism Disorder

In normal cardiomyocytes, Ca2+ mostly exists in the sarcoplasmic reticulum, mitochondria and sarcolemma, and plays an important role in the excitation-contraction coupling of cardiomyocytes. Anthracyclines-induced cardiotoxicity is associated with the dysregulation of Ca2+ level. The impaired Ca2+ homeostasis acts as a reason for reactive oxygen species generation [20]. Anthracyclines can act on cardiomyocytes, activate the Ca2+ channels in the sarcoplasmic reticulum and increase the amount of Ca2+ released from the sarcoplasmic reticulum to the cytoplasm [30]. The increase of intracellular free Ca2+ concentration can affect the electrical activity of cardiomyocytes, leading to various types of arrhythmias. Anthracyclines can also inhibit the gene expression of Ca2+-ATPase on the sarcoplasmic reticulum of cardiomyocytes, there by affecting the biosynthesis of Ca2+-ATPase, reducing its activity, reducing the ability of the sarcoplasmic reticulum to absorb Ca2+ and reducing the production of ATP by mitochondria, myocardial energy metabolism disorders, aggravate cell damage, and even lead to myocardial cell death [31]. Ca2+ can increase the expression of NF-kB by activating p38MAP kinase and JNK pathway and activate pro-apoptotic genes such as BAX and BAD, resulting in causing apoptosis and inflammation [32] (Figure 1).