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 This has been the case of several first-generation anti-depressants eventually withdrawn from the market, directly interacting with sodium, calcium, and potassium channels.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!