Cyp1 Inhibition Prevents Doxorubicin‐Induced Cardiomyopathy in a Zebrafish Heart‐Failure Model

Lam, Pui-ying; Kutchukian, Peter S.; Anand, Rajan; Imbriglio, Jason E.; Andrews, Christine L.; Padilla, Hugo; Vohra, Anita; Lane, Sarah; Parker, Dann L.; Cornella-Taracido, Ivan; Johns, Douglas G.; Beerens, Manu; MacRae, Calum A.; Caldwell, John P.; Sorota, Steve; Asnani, Aarti; Peterson, Randall T.

doi:10.1002/cbic.201900741

Cited by 19 publications

(17 citation statements)

References 9 publications

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“…Therefore, CYP2J2 may not be a reasonable therapeutic target in cardio-oncology. On the other hand, CYP1A1 has been shown to contribute to both anthracycline-induced cardiotoxicity [110][111][112][113] and tumor progression and survival of cancer cells [114,115]. Therefore, similar to CYP1B1, CYP1A1 may also be a reasonable therapeutic target in cardio-oncology.…”

Section: Role Of Cyp1b1 In Cardiovascular Diseasesmentioning

confidence: 99%

“…Although this lack of selectivity toward CYP1B1 may be undesirable from a mechanistic point of view, it may offer a therapeutic advantage since CYP1A1 is also a reasonable target in cardio-oncology as discussed earlier. Indeed, a number of studies have reported a protective effect of CYP1 inhibitors without discerning the protective effects to either CYP1A1 or CYP1B1 [112,113]. That being said, 2,4,3 ,5 -tetramethoxystilbene (TMS) exhibited 50-fold selectivity for CYP1B1 over CYP1A1 and 500-fold selectivity for CYP1B1 over CYP1A2 [146].…”

Section: Cyp1b1 Inhibitorsmentioning

confidence: 99%

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CYP1B1 as a therapeutic target in cardio-oncology

2020

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Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

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Section: Role Of Cyp1b1 In Cardiovascular Diseasesmentioning

confidence: 99%

Section: Cyp1b1 Inhibitorsmentioning

confidence: 99%

CYP1B1 as a therapeutic target in cardio-oncology

2020

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“…An example of a cardiotoxic agent is doxorubicin, a highly effective chemotherapy drug, the use of which is limited by cumulative, dose-related myocardial damage which can lead to heart failure. Using a zebrafish model of doxorubicin-induced cardiomyopathy for small-molecule screening, cytochrome P450 family 1 (CYP1) has been recently identified as a candidate therapeutic target for clinical cardioprotection 148,149 . Zebrafish, first introduced as a developmental model in 1970s, have become an increasingly attractive and valuable model for studying human diseases.…”

Section: Cardiovascular Drug Discovery and Future Directionsmentioning

confidence: 99%

Zebrafish as a tractable model of human cardiovascular disease

Bowley

Kugler

Wilkinson

et al. 2021

British J Pharmacology

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Mammalian models including non-human primates, pigs and rodents have been used extensively to study the mechanisms of cardiovascular disease. However, there is an increasing desire for alternative model systems that provide excellent scientific value while replacing or reducing the use of mammals. Here we review the use of zebrafish, Danio rerio, to study cardiovascular development and disease. The anatomy and physiology of zebrafish and mammalian cardiovascular systems are compared, and we describe the use of zebrafish models in studying the mechanisms of cardiac (e.g. congenital heart defects, cardiomyopathy, conduction disorders, regeneration) and vascular (endothelial dysfunction and atherosclerosis, lipid metabolism, vascular ageing, neurovascular physiology and stroke) pathologies. We also review the use of zebrafish for studying pharmacological responses to cardiovascular drugs, and describe several features of zebrafish that make them a compelling model for in vivo screening of compounds for the treatment cardiovascular disease.

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“…Acute doxorubicin toxicity has been particularly well studied in zebrafish, whereby a dose of doxorubicin 100 μM added to the embryo medium results in pericardial edema, decreased blood flow through the tail vasculature, and decreased cardiac contractility that can be visualized using a standard light microscope [ 7 ]. Our laboratory used this model to identify Cytochrome P450 Family 1 enzymes as an important therapeutic target in anthracycline cardiomyopathy [ 8 , 72 ], not only in acute cardiotoxicity but also in chronic doxorubicin cardiomyopathy models in adult mice. A chronic model of doxorubicin cardiomyopathy has also been developed in adult zebrafish, whereby hearts from fish treated with doxorubicin exhibited myofibril disarray and fetal cardiac gene expression [ 73 ].…”

Section: Zebrafish As a Model For Cancer Therapy-associated Cardiomentioning

confidence: 99%

“…Genetic knockout models can be created to investigate a cardiotoxic drug’s mechanism of action and target. For instance, a chemical screen in zebrafish enabled the identification of Cyp1 enzymes in anthracycline cardiotoxicity, and mutation of the Cyp1 active site using CRISPR/Cas9 prevented the development of cardiotoxicity in fish [ 72 ]. One could envision using zebrafish to study variants associated with cardiotoxicity in human genome-wide association studies.…”

Section: Zebrafish As a Model For Cancer Therapy-associated Cardiomentioning

confidence: 99%

Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

Lane

Asnani

2021

JCDD

Self Cite

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Purpose of review: Both traditional and novel cancer therapies can cause cardiovascular toxicity in patients. In vivo models integrating both cardiovascular and cancer phenotypes allow for the study of on- and off-target mechanisms of toxicity arising from these agents. The zebrafish is the optimal whole organism model to screen for cardiotoxicity in a high throughput manner, while simultaneously assessing the role of cardiotoxicity pathways on the cancer therapy’s antitumor effect. Here we highlight established zebrafish models of human cardiovascular disease and cancer, the unique advantages of zebrafish to study mechanisms of cancer therapy-associated cardiovascular toxicity, and finally, important limitations to consider when using the zebrafish to study toxicity. Recent findings: Cancer therapy-associated cardiovascular toxicities range from cardiomyopathy with traditional agents to arrhythmias and thrombotic complications associated with newer targeted therapies. The zebrafish can be used to identify novel therapeutic strategies that selectively protect the heart from cancer therapy without affecting antitumor activity. Advances in genome editing technology have enabled the creation of several transgenic zebrafish lines valuable to the study of cardiovascular and cancer pathophysiology. Summary: The high degree of genetic conservation between zebrafish and humans, as well as the ability to recapitulate cardiotoxic phenotypes observed in patients with cancer, make the zebrafish an effective model to study cancer therapy-associated cardiovascular toxicity. Though this model provides several key benefits over existing in vitro and in vivo models, limitations of the zebrafish model include the early developmental stage required for most high-throughput applications.

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Cyp1 Inhibition Prevents Doxorubicin‐Induced Cardiomyopathy in a Zebrafish Heart‐Failure Model

Cited by 19 publications

References 9 publications

CYP1B1 as a therapeutic target in cardio-oncology

CYP1B1 as a therapeutic target in cardio-oncology

Zebrafish as a tractable model of human cardiovascular disease

Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

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