Why would doxorubicin be fatal to a cell

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. Many drugs can affect doxorubicin. This includes prescription and over-the-counter medicines, vitamins, and herbal products.

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If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist. This information does not replace the advice of a doctor. Healthwise, Incorporated, disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. Learn how we develop our content. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated. In particular, significant differences between mouse and human cardiac system in terms of electrophysiology and contractile features limit the extrapolation of findings from studies in murine systems to humans 29 , Recently, human pluripotent stem cell-derived cardiomyocytes hiPS-CMs have emerged as a powerful tool to model cardiac toxicity in highly physiologically relevant human cells 31 , 32 , In this study, we investigated drug-induced cardiotoxicity using iPS-CMs assay system.

We made novel findings to implicate DR-mediated apoptosis in doxorubicin-induced cardiotoxicity. In clinical settings, doxorubicin can induce cell death of cardiomyocytes in some patients within hours of intravenous administration We investigated doxorubicin-induced cytotoxicity in iPS-derived cardiomyocytes. Cells were grown onto fibronectin coated plates and exposed to doxorubicin at increasing doses. The resulting cells were analyzed using orthogonal assays for cell viability, apoptosis, and the release of cardiac factors.

As expected, doxorubicin treatment resulted in a dose-dependent decrease in cell viability with an IC50 of 3. An increase in apoptotic cell population was detected by the positive immunostaining of active caspase-3 data not shown , an increase in DNA fragmentation Fig.

Further, there was a simultaneous release of cardiac troponin I cTnI Fig. Overall, these data are in agreement with previous reports from cellular and human biopsy studies demonstrating doxorubicin-induced cardiotoxicity The data support the use of the iPS-derived cardiomyocytes as a human cellular model to assess the potential cardiotoxicity of anticancer agents.

The resulting cells were analyzed for cell viability a , DNA fragmentation b , caspase activation c , and cTnI release d. To gain insight into the molecular mechanisms involved in doxorubicin induced cardiotoxicity, we determined the expression of death receptors in iPS-derived cardiomyocytes.

A similar observation was made for structurally related compounds within the anthracycline family, including daunorubicin, idarubicin, and epirubicin Fig. By sharp contrast, sunitinib a tyrosine kinase inhibitor showed little or no effect on any of the DRs tested. At the transcriptional level, the mRNA expression of all four DRs displayed at least a 2-fold increase in iPS-derived cardiomyocytes treated with doxorubicin or daunorubicin Fig.

The expression of several pro-apoptotic genes such as caspase 3, caspase 8, FADD was also elevated, albeit to a lesser extent data not shown. These data demonstrate that doxorubicin, as well as related anthracycline family compounds, potently induce the expression of DRs at both mRNA and protein levels in iPS-derived cardiomyocytes.

In cancer cells, overexpression of DRs was shown to cause receptor clustering on cell membrane thereby triggering activation of a caspase cascade and subsequent apoptosis A similar mode of action may occur in iPS-CMs upon doxorubicin treatment, leading to spontaneous apoptosis of the cardiomyocytes Fig.

Under physiological conditions, individual DRs respond to their cognate ligands e. There is also evidence that doxorubicin induced the release of FasL from rat cardiomyocytes, which may provide feedback signaling to kill target cells through the upregulated DRs 27 , Notably, this cytotoxicity effect was effectively blocked by pretreating the cells with a DR5 neutralizing antibody Fig. This data supports the notion that DR5 upregulation may be a critical mechanism in doxorubicin induced cardiotoxicity.

This was further confirmed when the iPS-CMs were treated with a combination of the death ligands Fig. Clinical use of doxorubicin has been associated with various arrhythmias by affecting the electrophysiological characteristics of cardiomyocytes Consistent with the data in Fig. Taken together, these data suggest that TRAIL might be directly involved in the execution of doxorubicin induced cardiotoxicity under physiologically relevant conditions.

The resulting cells were monitored for cell index b , beating patterns c , beating rate d and beating amplitude e. A body of evidence establishes iPS-derived cardiomyocytes as an in vitro assay system to model drug-induced cardiotoxicity 42 , This human cellular model recapitulates many of the known cardinal features of cardiotoxicity observed in humans thereby allowing a physiologically accurate dissection of the adverse drug action Using iPS-CMs assays, we identified a novel mechanism by which doxorubicin elicits toxicity in cardiomyocytes.

Similar effects were also found for other anthracyclines, including daunorubicin, idarubicin, and epirubicin. Anthracyclines appear to potently induce the expression of death receptors in cardiomyocytes, resulting in spontaneous or ligand-dependent apoptosis in target cells. These data suggest that the elevated serum levels of specific TNF cytokines could be predictive of the risk of doxorubicin-induced cardiotoxicity in individual patients Fig.

Additional studies are warranted to evaluate the causal relationship between the baseline serum levels of specific TNF cytokines and the adverse cardiac events in patients receiving doxorubicin treatment. These data also support the utility of the iPS-CMs cellular system for high throughput screening of novel cardioprotective agents to mitigate the cardiotoxicity of doxorubicin and other anthracyclines. The upregulated DRs may undergo clustering or engage their cognate ligands, thereby triggering a caspase cascade and ultimate apoptosis in cardiomyocytes.

The elevated serum levels of specific TNF cytokines e. These cellular events are thought to trigger intrinsic apoptosis in cardiomyocytes. Under physiological conditions, TNF-related cytokines are known to play an important role in maintaining tissue homeostasis. These cytokines can engage their corresponding death receptors TNFR1, Fas, DR4, and DR5 expressed on cell membrane, leading to activation of a caspase cascade and ultimate cell death — a process known as extrinsic apoptosis.

Notably, the extrinsic apoptosis machinery is conserved in cardiomyocytes across animal species. One report suggested that the elevated TNFR1 expression was positively associated with doxorubicin-induced apoptosis in rat cardiomyocytes The upregulated DRs may undergo clustering on the cell surface, leading to spontaneous apoptosis Fig.

Nonetheless, the ability of doxorubicin to upregulate DRs in cardiomyocytes provides critical insight into the molecular mechanisms of the adverse drug reaction. The above findings could help identify biomarkers to predict the risk of cardiotoxicity in individual patient prior to the administration of doxorubicin or other anthracyclines. Currently, multiple strategies are clinically used for prevention and early detection of anthracycline-induced cardiomyopathy These include the measurement of serum cardiac troponins cTnT and cTnI that are closely associated with the severity of myocardial damage in patients treated with doxorubicin or other chemotherapy 54 , The elevated TnT levels were shown to be predictive of subsequent left ventricular dilation and left ventricular wall thinning identified by echocardiography However, it is recognized that a broad range of conditions are associated with the raised cTnT and cTnI values which causes diagnostic confusion and clinical dilemmas in patient management.

Moreover, the serum cTnT and cTnI levels are only raised after cardiac damage or dysfunction had occurred. There is an unmet need for biomarkers that can predict potential cardiotoxicity before the onset of adverse cardiac events Our data show that the TNF-related cytokines, in particular TRAIL, could augment doxorubicin-induced cardiotoxicity by engaging the upregulated death receptors on the cardiomyocytes Fig.

However, these observations were made under the specific in vitro conditions with recombinant death ligand proteins. In light of the presence of TNF cytokines in circulation, whose serum levels can be very different among patients based on the status of disease and the history of treatment, we hypothesize that the elevated serum levels of TNF cytokines could help identify patient populations at a higher risk to doxorubicin associated cardiotoxicity.

Investigations are underway in our laboratory to evaluate the causal relationship between the baseline serum levels of specific TNF cytokines and the adverse cardiac events in cancer patients receiving doxorubicin treatment.

Meanwhile, frozen vials of Cor. The plates containing Cor. Culture medium was refreshed daily without disturbing cell attachment. Under these culture conditions, Cor. Doxorubicin hydrochloride Catalog D , epirubicin hydrochloride E , idarubicin hydrochloride I and sunitinib malate PZ were purchased from Sigma-Aldrich St. Louis, MO.

On Day 4, cells were treated with doxorubicin or other drugs see details in Figure legends. The levels of lactate dehydrogenase 25 , a cytosolic enzyme that is released into culture medium upon plasma membrane damage, were determined using a LDH Cytotoxicity Assay Kit from ThermoFisher Scientific Rockville, MD. The OD values in treated samples were compared with those values obtained from untreated control cells, and expressed as apoptosis fold changes.

When Cor. The baseline signal in the untreated Cor. After the data acquisition, the RTCA Cardio software is used to calculate the parameters such as normalized beating rate and amplitude with statistical analysis.

How to cite this article : Zhao, L. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rochette, L. You may gain weight while having this treatment. You may be able to control it with diet and exercise. Tell your doctor or nurse if you are finding it difficult to control your weight. There isn't enough information to work out how often these side effects might happen. You might have:. Cancer drugs can interact with some other medicines and herbal products. Tell your doctor or pharmacist about any medicines you are taking.

This includes vitamins, herbal supplements and over the counter remedies. This drug may harm a baby developing in the womb. It is important not to become pregnant or father a child while you are having treatment with this drug and for at least 6 months afterwards.

Talk to your doctor or nurse about effective contraception before starting treatment. You may not be able to become pregnant or father a child after treatment with this drug. Talk to your doctor before starting treatment if you think you may want to have a baby in the future.

Men might be able to store sperm before starting treatment. And women might be able to store eggs or ovarian tissue. But these services are not available in every hospital, so you would need to ask your doctor about this. Tell your doctor if you have had radiotherapy treatment to your chest that might have been near to or involving your heart.

This could increase the risk of heart damage from doxorubicin and your doctor will need to take this into account. Rarely you might have skin changes in an area where you have had radiotherapy. Talk to your team about this. The length of time depends on the treatment you are having. Ask your doctor or pharmacist how long you should avoid live vaccinations. Contact with others who have had immunisations - You can be in contact with other people who have had live vaccines as injections.

Avoid close contact with people who have recently had live vaccines taken by mouth oral vaccines such as the oral typhoid vaccine. If your immune system is severely weakened, you should avoid contact with children who have had the flu vaccine as a nasal spray. This is for 2 weeks following their vaccination. Babies have the live rotavirus vaccine. Unfortunately, chemotherapy does not know the difference between the cancerous cells and the normal cells.

Chemotherapy will kill all cells that are rapidly dividing. Different drugs may affect different parts of the body. Doxorubicin is classified as an antitumor antibiotic. Antitumor antibiotics are made from natural products produced by species of the soil fungus Streptomyces. These drugs act during multiple phases of the cell cycle and are considered cell-cycle specific. There are several types of antitumor antibiotics:.

Note: We strongly encourage you to talk with your health care professional about your specific medical condition and treatments. The information contained in this website is meant to be helpful and educational, but is not a substitute for medical advice. For information about the 4th Angel Mentoring Program visit www. Toggle navigation. Spanish About Chemocare. How Doxorubicin Is Given: Doxorubicin is administered via an intravenous IV injection through a central line or a peripheral venous line, and the drug is given over several minutes.

Doxorubicin can also be given by continuous infusion through a central catheter line. There is no pill form of Doxorubicin. Doxorubicin is a vesicant. A vesicant is a chemical that causes extensive tissue damage and blistering if it escapes from the vein.

The nurse or doctor who gives Doxorubicin must be carefully trained. If you notice redness or swelling at the IV site while you are receiving Doxorubicin, alert your health care provider immediately. Side Effects: Important things to remember about the side effects of Doxorubicin: Most people will not experience all of the side effects listed.

Your white and red blood cells and platelets may temporarily decrease. Nadir: days Recovery: days Hair loss on the scalp or elsewhere on the body called alopecia.

Most patients do lose some or all of their hair during their treatment.