Cisplatin is a chemotherapeutic agent for a vast spectrum of cancers. However, its acute and cumulative cardiotoxicity partially limits anti-tumor treatment and clinical applications (Ma et al., 2010). Cisplatin-treated cardiomyocytes showed mitochondrial abnormalities such as mitochondrial membrane depolarization, inflammatory responses and increased ER stress, which finally stimulated the activity of caspase-3 and induced apoptosis (Chowdhury et al., 2016). In addition, emerging evidences demonstrated a close connection between oxidative stress and cisplatin-induced cardiomyocyte apoptosis. El-Awady el et al. (2011) discovered that cisplatin improved lipid peroxidation, decreased GSH content and suppressed SOD activity, implying oxidative stress induced by cisplatin. Moreover, mitochondrial DNA injury and nuclear DNA damage were observed. Antioxidant natural products such as tutin (vitamin P1), zingerone and cyanidin can inhibit cisplatin-induced inflammatory infiltration, DNA damage, and mitochondrial dysfunction, indicating the key role of oxidative stress in cisplatin-induced cardiomyocyte apoptosis (Qian et al., 2018; Soliman et al., 2018; Topal et al., 2018).

Cyclophosphamide is commonly applied in the treatment of malignant tumors such as leukemia and lymphoma, and it is also adopted to treat systemic lupus erythaematosus and polymyositis as an immunosuppressor. Because of the dose-dependent manner, cyclophosphamide-induced cardiotoxicity basically coincides with high-dose treatment (Nishikawa et al., 2015; Wadia, 2015). Acrolein, the active metabolite of cyclophosphamide, was confirmed to be mainly responsible for cardiomyocyte death (Conklin et al., 2015; Nishikawa et al., 2015; Kurauchi et al., 2017). The cardiomyocyte injuries caused by cyclophosphamide treatment included sarcoplasmic reticulum dilatation, mitochondrial disruption and nuclear membrane invagination (Lushnikova et al., 2008). Further studies attributed these injuries to oxidative stress, clarifying that acrolein caused oxidative and nitrite stress through the suppression of intracellular GSH and SOD and increase of MDA (Nagi et al., 2011; Kurauchi et al., 2017; Omole et al., 2018). Corresponding lipid peroxidation initiated mitochondrial function damage, which further led to a collapse in APT production and the activation of caspase-3, resulting in apoptosis (Nagi et al., 2011; Refaie et al., 2020). In addition, cyclophosphamide was verified to stimulate TLR4, through which it initiated the TLR4/NF-κB signaling to trigger an inflammatory reaction, and eventually apoptosis (El-Agamy et al., 2017). Furthermore, DNA damage was observed in cyclophosphamide-treated rats, which were accompanied with activation of caspase-3 and inhibition of Bcl-2 expression (Avci et al., 2017). Antioxidant drugs such as silymarin and curcumin can inhibit cyclophosphamide-induced cardiotoxicity via decreasing the fragments of mitochondrial DNA and nuclear DNA, suggesting that excessive ROS might be responsible for cyclophosphamide-induced DNA injuries.

With the exception of the evidence discussed above, cyclophosphamide acted as a teratogen to injure cardiomyocytes. Cyclophosphamide affected cardiomyocytes developing via DNA fragmentation degradation, caspase-3 activation and PARP cleavage (Mirkes and Little, 1998). Moreover, cyclophosphamide was found to activate the apoptotic pathways, culminating in abnormality of the heart via the p38-MAPK signaling (Mirkes et al., 2000).

5-Fluorouracil, a pyrimidine antimetabolite, is used widely in clinical practice as an anti-tumor treatment for cancers such as intestinal cancer and liver cancer. Capecitabin, a tumor-targeting drug that takes effect after the intracellular transformation into 5-fluorouracil, was regarded as having similar cardiotoxicity. Multiple studies confirmed the cardiotoxicity induced by 5-fluorouracil, which was attributed to the coronary arteries injury (Clavel et al., 1988; Herrmann et al., 2016). Further study suggested that the cardiomyocyte apoptosis might also play an important role in 5-fluorouracil-induced cardiotoxicity (Tsibiribi et al., 2006). 5-Fluorouracil stimulated intracellular oxidative stress by O₂^– generation, which eventually activated the caspases cascade reactions, leading to apoptosis (Lamberti et al., 2012). To further determine the underlying mechanism, Eskandari et al. (2015) discovered that 5-fluorouracil-induced ROS increase was accompanied by the depletion of GSH, a ROS scavenger. Next, the generated ROS mediated lipid peroxidation on mitochondria to decrease MMP, causing mitochondrial dysfunction and caspase-3 activation. Fluoroacetate, the metabolite of 5-fluorouracil, can restrain aconitase to block the tricarboxylic acid cycle, resulting in a mitochondrial energy metabolism crisis (Lischke et al., 2015). Moreover, accumulation of autophagosomes and lysosomal membrane leakiness were observed in 5-fluorouracil-treated human cardiomyocytes, indicating the involvement of autophagic cell death in 5-fluorouracil-induced cardiotoxicity (Eskandari et al., 2015; Focaccetti et al., 2015).

Arsenic trioxide represents a breakthrough in the field of acute promyelocytic leukemia therapeutic, but its cardiotoxicity remains an unresolved problem. In the past few decades, numerous studies have proposed that cardiomyocyte apoptosis is induced by ROS, and mitochondrial damage might be the main reason for arsenic trioxide-induced cardiotoxicity (Zhao et al., 2008; Raghu and Cherian, 2009; Vineetha et al., 2015). Arsenic trioxide can increase ROS level and calcium concentration, which was accompanied with cardiomyocyte apoptosis (Raghu and Cherian, 2009). Moreover, ROS generation depleted intracellular antioxidants such as GSH, GSH-Px, glutathione s-transferase (GST) and SOD, which caused lipid peroxidation and decreased MMP (Varghese et al., 2017). In addition, mitochondrial damage such as MTP and mitochondrial swelling was also observed under arsenic trioxide exposure, following by a decrease in oxygen consumption as well as ATP production, resulting in caspase-3 activation and apoptosis (Vineetha et al., 2015). Recently, Li et al. (2019) found that arsenic trioxide interfered with the dynamic balance of trace elements in chicken cardiomyocytes to break mitochondrial cristae and mitochondrial vacuoles, increasing the expressions of Bax and caspase-3/8. In addition to ROS and mitochondrial damage, calcium imbalance is also involved in arsenic trioxide-induced cardiotoxicity. Arsenic trioxide suppressed the activity of sarcoplasmic reticulum Ca²⁺-ATPase2a, by which cytoplasmic calcium was taken back to the sarcoplasmic reticulum (Zhang J.Y. et al., 2016). Consequently, the imbalance of calcium homeostasis and ER stress activated C/EBP-homologous protein (CHOP), caspase-12 and GRP78, leading to apoptosis.

By increasing the levels of the inflammatory cytokines TNFα, NF-κB, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), arsenic trioxides promoted the inflammatory reactions and brought ultrastructural damage to cardiomyocytes (Li et al., 2017). These inflammatory responses partly contributed to heavy metal-related cardiotoxicity (Lakkur et al., 2015). Additionally, it has been determined that arsenic trioxides up-regulates the content of phosphorylated p38 and JNK by oxidative stress stimulation and calcium overload, which further induces NF-κB phosphorylation, caspase-3 activation and PARP cleavage (Ghosh et al., 2009; Fan et al., 2013). Suppression of ROS apparently inhibited the activation of JNK, extracellular regulated protein kinases (ERK), and p38, which eventually reversed cardiomyocyte apoptosis (Miao et al., 2013; Zhang et al., 2017). One recent study reported that arsenic trioxides might induce cardiomyocyte apoptosis through DNA damage, since it dose-dependently increased the content of γH2AX, a sensitive biomarker for DNA breaks (Bao et al., 2019). Moreover, activation of Parkin, an E3 ubiquitin ligase, can inhibit arsenic trioxide-induced cardiotoxicity via the maintenance of mitochondrial as well as cellular homeostasis (Watanabe et al., 2014). It is well known that Parkin-induced ubiquitination of mitochondrial substrates finally leads to mitophagy. Therefore, mitophagy displays a positive role in maintaining cardiac homeostasis during arsenic trioxide exposure. However, a subsequent study demonstrated that arsenic trioxide-induced oxidative stress led to the formation of autophagosomes through PI3K/Akt/mTOR signaling, which resulted in myocardial damage (Li S. et al., 2018; Zhao et al., 2019). Moreover, cardiomyocyte necrosis was also observed under arsenic trioxide exposure (Raghu and Cherian, 2009; Vineetha et al., 2015), but the underlying mechanisms remained unclear.

A novel and widely used monoclonal antibody drug, Trastuzumab, is also reported to cause cardiotoxicity, such as cardiac insufficiency and heart failure. Under physiological condition, neuregulin-1 interacted with epidermal growth factor receptor-2 (ErbB2) to allow for the formation of ErbB4/ErbB2 heterodimer, which blocked cell death through an Akt-dependent signaling in cardiomyocytes (Sawyer et al., 2002; Lemmens et al., 2007). Functioning as an inhibitor of ErbB2 receptor, trastuzumab interrupted ErbB4/ErbB2 heterodimerization, thereby leading to apoptosis (Holbro and Hynes, 2004; Rohrbach et al., 2005). Interaction between Trastuzumab and ErbB2 triggered the downstream signal transduction pathways, such as increased levels of Bax and Bcl-xS, decreased Bcl-xL level and caspases cascade activations. Furthermore, the decreased MMP caused by Bcl-xL suppression and subsequent mitochondrial energy catastrophe also contributed to trastuzumab-induced apoptosis (Grazette et al., 2004). Singh et al. (2011) proposed that the cardiotoxicity induced by trastuzumab might stem from its negative regulation of murine double minute 2 (MDM2) and p53. In addition, trastuzumab-induced cardiomyocyte apoptosis was found to be related to inflammatory infiltration (Coppola et al., 2016), and the TLR4-mediated chemokine expressions of TNFα, MCP-1 and ICAM-1 contributed to inflammatory responses induced by trastuzumab (Yousif and Al-Amran, 2011).

A recent study reported that trastuzumab suppressed autophagy, resulting in mitochondrial dysfunction and ROS accumulation (Mohan et al., 2017). Trastuzumab insult inhibited the expressions of Beclin 1, autophagy related gene (Atg) 5-12 and Atg14. Moreover, Trastuzumab stimulated EebB1-Y845 and ErbB2-Y1248 and activated the ERK/mTOR/ULK-1 signaling to supress autophagy (Mohan et al., 2016).

Currently, drug combination therapies with trastuzumab are quite popular among cancer treatment plans. However, the combination therapies show more serious cardiotoxicity compared with single drug remedies. Trastuzumab combining with DOX exacerbated the exhaustion of antioxidant enzymes as well as damage to the mitochondrial structure (Xu et al., 2004). Trastuzumab-induced ErbB2 inhibition further suppressed c-Abl and Arg, which plays an antioxidant role by activating GSH-Px and catalase, thereby increasing DOX-induced cytotoxicity (Belmonte et al., 2015). Additionally, inhibition of the neuregulin-ErbB signaling by trastuzumab restrained the phosphorylation of ERK1/2 and Akt, and eventually exacerbated DOX-induced cardiomyocyte apoptosis and myocardial fiber injury (Sawyer et al., 2002). The underlying mechanism might also include the increased level of iNOS, which contributed to oxidative stress and inflammatory cell infiltration (Milano et al., 2020). Moreover, DOX-trastuzumab combination synergistically repressed Top2β, and eventually resulted in DNA double strand breaks and the ROS overproduction (Jiang et al., 2018). N-Acetyl Cysteine Amide, a ROS scavenger, can attenuate the DOX and trastuzumab-induced cardiac dysfunction (Goyal et al., 2016). Furthermore, paclitaxel-trastuzumab combination was reported to have a worsening effect on cardiomyocyte function, which might result from the inhibition of phosphorylated-ERK1/2. However, no cell death was observed during treatment in addition to myofibrillar structure changes (Pentassuglia et al., 2007).

Tyrosine-kinase inhibitors such as sunitinib, imatinib, nilotinib, sorafenib, ponatinib, and dasatinib are widely applied for chronic myelogenous leukemia and solid tumors, however, an increasing number of studies have reported cardiotoxicity associated with tyrosine-kinase inhibitors. Clinical research observed aberrantly shaped, swollen mitochondria in cardiomyocytes of patients who developed congestive heart after sunitinib treatment (Chu et al., 2007). Bouitbir et al. (2019) demonstrated that the oxidative stress caused by sunitinib was mainly responsible for the mitochondrial damage and final apoptosis of cardiomyocytes. By suppressing mitochondrial electron transport chain enzyme complexes, sunitinib induced ROS accumulation, which further decreased MMP and destroyed the mitochondrial structure to initiate caspases cascade reactions. In addition, sunitinib was confirmed to increase the expression of miR-133A, and suppress the apoptosis signal-regulating kinase 1 (ASK1)/mitogen activated kinase kinase 7 (MKK7)/JNK signaling to induce apoptosis and myocardial damage (Cooper et al., 2018). The elevation of autophagy flux was observed in sunitinib-treated H9c2 cells, (Zhao et al., 2010), and inhibition of autophagy was demonstrated to attenuate sunitinib-induced cardiotoxicity (Kimura et al., 2017), indicating involvement of autophagy in the cytotoxicity.

Mitochondrial damage was also observed in imatinib-treated cardiomyocytes. Imatinib down-regulates the expression of Bcl-2 and Bcl-xL by suppressing the content of the transcription factor GATA4, resulting in apoptosis. Moreover, aging was verified to be a risk factor during imatinib treatment because of its positive impact on the oxidative stress (Maharsy et al., 2014). In addition, Chambers et al. (2017) showed that imatinib induced oxidative stress and mitochondrial dysfunction via mediating JNK-related mitochondrial signaling and activating caspase-3/7/9. Autophagic death was also reported to be associated with imatinib-induced cardiotoxicity (Hu et al., 2012). Imatinib blocked the autophagic process as indicated by an increased level of lysosomes, which was consistent with the accumulation of p62, a protein degraded by autophagic clearance.

As a second-generation Bcr-Abl inhibitor, nilotinib mediated apoptosis mainly through the accumulation of ROS and ER stress (Doherty et al., 2013). The increase of ROS and ER stress biomarkers (ATF4 and CHOP), was observed in nilotinib-treated H9c2 cells, which subsequently decreased MMP and activated caspase-3, markers of apoptosis (Lekes et al., 2016). Recently, Yang et al. (2018) made further efforts to demonstrate that nilotinib induced ER stress to activate JNK and restrain Akt phosphorylation, which in turn suppressed glycogen synthase kinase-3 beta (GSK3β) phosphorylation and activated NOX4/ROS signaling, resulting in apoptosis.

Few studies reported potential apoptosis mechanisms associated with sorafenib, ponatinib and dasatinib. Cheng et al. (2011) demonstrated that sorafenib induced cardiomyocyte apoptosis and cardiotoxicity by inhibiting the Raf/MEK/ERK signaling. In addition, cardiomyocytes necrosis was observed during high-dose sorafenib treatment with unclear mechanism (Duran et al., 2014). The most recent study reported that ponatinib inhibited phosphorylation of Akt and ERK1/2, which contributed to the activation of pro-apoptotic caspase-3 (Singh et al., 2019). Xu et al. (2018) found that dasatinib dose-dependently up-regulated intracellular HMGB1 to induce cardiomyocyte necroptosis.

With similar structure to DOX, mitoxantrone was thought to be an alternative to DOX with less cardiotoxicity (Herman et al., 1997). However, several studies have also reported mitoxantrone-induced cardiotoxicity. Mitoxantrone induced cardiomyocyte apoptosis associated with oxidative stress and mitochondrial dysfunction. With a time-dependent increase in the content of ROS, mitoxantrone promoted the accumulation of calcium and decreased the MMP, which further caused mitochondrial energy deficiency and activated caspase-3 (Rossato et al., 2013). In addition, DNA strand breaks were observed in apoptotic H9c2 cells treated with mitoxantrone, which was probably mediated by a Top2β-dependent signaling (Wu et al., 2013; Damiani et al., 2018).

Rosiglitazone and pioglitazone, as thiazolidinedione antidiabetic agents, were regarded as protective agents in diabetic cardiomyopathy and ischaemia-reperfusion injury (Cao et al., 2007; Baraka and Abdelgawad, 2010). However, with further expansion of their clinical applications, rosiglitazone and pioglitazone are also found to cause serious side effects such as myocardial hypertrophy and heart failure. It has been reported that rosiglitazone exerts both protective and detrimental effects in rats treated by ischaemia reperfusion (Palee et al., 2013). Although rosiglitazone was known as a PPARγ agonist, it caused cardiotoxicity via oxidative stress-induced mitochondrial dysfunction independent of PPARγ. By increasing the levels of NAPHD and iNOS, rosiglitazone induced oxidative stress accompanied by the exhaustion of antioxidant enzymes such as SOD and glutathione reductase, resulting in cardiotoxicity apoptosis (Mishra et al., 2014). In addition, the oxidative effect caused mitochondrial dysfunction, followed by cardiomyocyte energy deficiency (He et al., 2014). For pioglitazone, a study once reported that pioglitazone up-regulated the levels of sphingomyelinase and ceramidase, a mediator of cardiomyocyte apoptosis (Baranowski et al., 2007). Moreover, by activating Bax and phosphorylated p53 as well as suppressing phosphorylated Akt and mTOR, pioglitazone could induce apoptosis in a VEGFR-2 dependent manner (Zhong et al., 2018).

Zidovudine, like other nucleoside reverse transcriptase inhibitors, is widely used for human immunodeficiency virus type 1 (HIV-1) infection. However, side effects such as hypertension and cardiomyopathy limit its long-term application. Zidovudine stimulated the accumulation of ROS and peroxynitrite, which in turn gives rise to single-strand DNA breaks, and eventually results in mitochondrial energy depletion in a NAD⁺-dependent manner (Szabados et al., 1999). Zidovudine induced the transport of protein kinase C δ (PKCδ) from the cytosol to the membrane, which promoted the activation of NADPH oxidases (Papparella et al., 2007). Meanwhile, mitochondrial damage is observed after zidovudine treatment (Fiala et al., 2004). Mitochondrial ROS caused by zidovudine played a significant role in mitochondrial disruption-induced apoptosis by activating caspase-3/7 (Ry et al., 2011). Fas/Fas L was also involved in zidovudine-induced cardiomyocytes apoptosis (Purevjav et al., 2007). Besides the above effects, zidovudine was shown to inhibit autophagosome maturation and decrease autophagic flux, leading to mitochondrial membrane polarization and ROS accumulation (Lin et al., 2019). Zidovudine-induced cardiomyocyte necrosis involved PARP activation (Gao et al., 2011).