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Cardiotoxic drugs and mechanisms of cardiotoxicity

Rosaria Esposito
Tags: Drug Discovery, Toxicology,

The discovery of penicillin changed the course of medicine and it is, probably for this very reason, one of the most famous examples of drug discovery. What is maybe less known is that it took at least 15 years from the moment Sir Alexander Fleming observed for the first time that his Staphylococcus aureus colonies did not grow around a fungus contaminating his Petri dish in 1928 to the moment penicillin was actually rendered available for mass distribution in 1944. Certainly, the challenges that Fleming had to overcome, in particular the difficulty in producing the promising medicament in amounts sufficient for in vivo testing, are not the same in the modern era. This length of time still reflects the long winding path of drug discovery extremely well. Even though we are now capable of better handling the purification/production phases, the process to introduce a new drug into the market is complex and highly time-consuming (not to mention expensive).

Figure 1 depicts the main steps of drug development, a process typically lasting more than ten years. It starts with thousands of potential drug candidates, eventually reduced to one (or very few) molecule(s) approved by the regulatory agencies. This tight funnel is related not only to the effectiveness of the molecules but also to safety issues. It is, indeed, estimated that drug toxicity is responsible for the attrition of one in three drug candidates (1). Therefore, predictive toxicology studies are necessary to anticipate and characterize possible adverse effects.

Compounds metabolism in the organism and off-target activities are amongst the most common causes of toxic reactions. Since the liver is the primary site of detoxification, hepatotoxicity studies are a priority in this context. Still, potential impacts on other organs and systems need to be evaluated as well (e.g., cardiovascular toxicity, nephrotoxicity, neurotoxicity, etc.). In particular, cardiotoxicity represents one of the most severe side effects associated with drug development. It limits the efficacy of useful therapeutics and has led to the post-marketing withdrawal of numerous others: almost 10% of drugs in the last four decades have been recalled from the clinical market worldwide due to cardiovascular safety concerns (2). Unfortunately, the lack of a complete understanding of the mechanisms underlying these adverse reactions makes it difficult to efficiently reveal cardiotoxicity in the preclinical phase of the development of medicinal products, hence the increasing attention to the development of suitable models and reliable tests to overcome this limitation.

Which drugs can have cardiotoxic effects?

Cardiotoxic events can be associated with almost all therapeutic drug classes, including those targeting common conditions, such as antibiotics, antivirals, or anti-inflammatory drugs. However, great attention is devoted to cardiotoxicity induced by chronically administered treatments, such as neurologic/psychiatric agents, as a progressive accumulation of the drug or its metabolites may induce long-term effects, more difficult to foresee in preclinical phases. It is also worth mentioning that, with cancer being the second leading cause of death worldwide, the well-established toxic effect of chemotherapeutic agents on the cardiovascular system concerns a relatively high proportion of the population. This concern led to the development of a new research field: cardio-oncology (or onco-cardiology), which focuses on the detection, monitoring, and treatment of cardiovascular disease occurring as a side effect of chemotherapy and radiotherapy (3).

What are the drug-induced cardiotoxic events?

Cardiomyopathies, potentially progressing into heart failure, are among the significant adverse events one can observe. However, drug-induced cardiotoxicity can affect the cardiovascular system from basically any angle. In fact, common clinical manifestations concern the function or the integrity of the heart itself (myocardial ischemia, myocarditis, arrhythmias, fibrosis, etc.) and the vascular system (hypertension, thromboembolism, vasospasm, etc.). A deeper understanding of the mechanisms behind these toxic manifestations is fundamental in developing more adapted therapeutic protocols and reducing risks for patients.

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Figure 1. Overview of the main steps involved in the drug discovery process. The thousands of compounds typically included in the first phases are progressively selected based on their efficacy and safety.

What are the typical mechanisms underlying drug-induced cardiotoxicity?

The aforementioned pathological conditions are linked at the molecular level to various alterations of cellular homeostasis, often playing together in a tremendously complex game, of which we still ignore all the rules. Therefore, below are a few extremely simplified examples of key cellular processes susceptible to being negatively altered when one tries to interfere in the match with the addition of new players.

One of the leading causes of cardiotoxicity is the impairment of cardiomyocytes activity through modifications of their mitochondrial metabolism. Because of the enormous amount of energy required to keep beating, the heart contains a higher number of mitochondria when compared to other organs. In this context, mitochondria are fundamental for calcium homeostasis related to cardiomyocytes contractility, the maintenance of the intracellular redox status, and the regulation of apoptosis/necrosis mechanisms. Multiple drug classes have been found to induce mitochondrial toxicity through different paths (4,5). For instance, a class of anti-cancer molecules called anthracyclines are known to be toxic to mitochondria because their direct target, TOP2B, is, unfortunately, also required for mitochondrial DNA replication.

Similarly, some local anaesthetics have been associated with cardiotoxicity because of collateral effects of their very action principle, that is, the reduction of nerve and heart cells' excitability via the interaction with sodium channels of the plasma membrane. Since they also affect the phospholipids on the mitochondrial membrane, they induce an increased mitochondrial membrane permeability, which in turn disrupts the electron transport chain.

On the other hand, some antiretroviral drugs (e.g., HIV treatment) have a mitotoxic effect associated with an off-target interaction. They are typically used to inhibit the viral reverse transcriptase but, as it turns out, they also inhibit the mitochondrial DNA polymerase gamma, thus disrupting mitochondrial function (4,5).

Heart muscle contraction requires the coordinated propagation of action potentials along the cell membrane of its cardiomyocytes. Therefore, all the drugs interfering with ion channel trafficking and thus with the electrophysiology of the heart can induce a cardiotoxic response. This has been the case of several first-generation anti-depressants eventually withdrawn from the market, directly interacting with sodium, calcium, and potassium channels. This off-target action is not surprising, considering that both nerve cells and cardiomyocytes exert their function via the propagation of an electric signal on their plasma membrane (5). The local anaesthetics mentioned above are another example of toxic effects associated with ion channel activity interference.

The alteration of growth signaling factors is a common strategy for cancer treatments, but it is also often associated with cardiotoxic effects (5). This is, for example, the case of Sorafenib and Vandetanib, two inhibitors of the VEGF (vascular endothelial growth factor) signaling pathway involved in both the angiogenesis associated with neoplastic metastasis and cardiomyocytes survival in response to environmental stress or disease. Similarly, therapeutic monoclonal antibodies developed to bind specific extracellular receptors to activate apoptosis and block tumor proliferation can adversely affect the cardiovascular system. One example is Trastuzumab, an ErbB2 receptor (HER2/neu) blocker also known to downregulate Neuregulin-1, a signaling molecule active in cardiac homeostasis and development. Its most common side effect is hypertension, but myocardial infarction may also occur (5).

What are Enzo tools to study cardiotoxicity?

As previously mentioned, to have a complete understanding of drug-induced cardiotoxicity mechanisms and be able to detect them as early as possible in the drug discovery process, sound model systems and adapted screening methods are required. Enzo's predictive toxicology portfolio, together with a rich selection of products dedicated to cardiovascular research, offers numerous tools supporting cardiotoxicity studies.

Do you need reference compounds for your predictive toxicology screening? Have a look at the SCREEN-WELL® Cardiotoxicity library, a selected collection of 130 compounds with defined and diverse cardiotoxic effects. An exciting application for this library was described in 2017 by Monteiro da Rocha , who used it to acquire information on the reliability of their in vitro model. They demonstrate that the maturation state of hiPSC-CMs (human-induced pluripotent stem cell-derived cardiomyocytes) is an important parameter to be taken into account for the applicability of pro-arrhythmia and cardiotoxicity findings to the adult heart (6).
If you are looking for a reliable and fast method to analyze the cellular response following toxic stress, the CELLESTIAL® catalog of fluorescent probes for live-cell analysis can be helpful. For example, Jiang et al. demonstrated that low-dose radiation can protect the heart from the cardiotoxic effects of doxorubicin, a drug commonly used to treat both solid and liquid tumors (7). In this work, the authors used Enzo's ROS-ID® Total ROS detection kit to monitor doxorubicin-induced oxidative stress on murine myocardial cells by flow cytometry.
Finally, to characterize the pathways specifically involved in cardiotoxic reactions, our ELISA kits might help detect markers of interest. This has been done, for instance, with Enzo's LTB4 ELISA kit in 2020 by Quagliarello et al., who tried to elucidate the molecular bases underlying the cardiotoxicity effects of Ipilimumab and Nivolumab, two immune checkpoint inhibitors used in cancer therapy (8).

Do you have questions on the available tools for your research? Do you need help in setting up your experiment? Want to learn more about our portfolio? Do not hesitate to reach out to our Technical Support Team. We will be happy to assist!

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  1. Guengerich FP. Mechanisms of Drug Toxicity and Relevance to Pharmaceutical Development. Drug Metab Pharmacokinet (2011). PMID: 20978361.
  2. Kelleni MT & Abdelbasset M. Drug Induced Cardiotoxicity: Mechanism, Prevention and Management. Link to the Chapter.
  3. Kostakou PM et al. Cardio-oncology: a new and developing sector of research and therapy in the field of cardiology Heart Fail Rev (2019). PMID: 30073443.
  4. Kim CW et al. Effects of anti-cancer drugs on the cardiac mitochondrial toxicity and their underlying mechanisms for novel cardiac protective strategies. Life Sci (2021). PMID: 33992675.
  5. Mamoshina P et al. Toward a broader view of mechanisms of drug cardiotoxicity. Cell Rep Med (2021). PMID: 33763655.
  6. Monteiro da Rocha A et al. hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen. Sci Rep (2017). PMID: 29061979.
  7. Jiang X. Low dose radiation prevents doxorubicin-induced cardiotoxicity. Oncotarget (2018). PMID: 29416617.
  8. Quagliariello V et al. Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models. J. Pers. Med. (2020). PMID: 33086484.

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