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

TY - JOUR

T1 - Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model

AU - Lam, Pui-Ying

AU - Kutchukian, Peter

AU - Anand, Rajan

AU - Imbriglio, Jason

AU - Andrews, Christine

AU - Padilla, Hugo

AU - Vohra, Anita

AU - Lane, Sarah

AU - Parker, Dann L

AU - Cornella Taracido, Ivan

AU - Johns, Douglas G

AU - Beerens, Manu

AU - MacRae, Calum A

AU - Caldwell, John P

AU - Sorota, Steve

AU - Asnani, Aarti

AU - Peterson, Randall T

N1 - © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2020/7/1

Y1 - 2020/7/1

N2 - Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, a zebrafish model of doxorubicin-induced cardiomyopathy was previously established for small-molecule screening. Using this model, several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish and in mouse models have previously been identified. In this study, exploration of doxorubicin cardiotoxicity is expanded by screening 2271 small molecules from a proprietary, target-annotated tool compound collection. It is found that 120 small molecules can prevent doxorubicin-induced cardiotoxicity, including 7 highly effective compounds. Of these, all seven exhibited inhibitory activity towards cytochrome P450 family 1 (CYP1). These results are consistent with previous findings, in which visnagin, a CYP1 inhibitor, also prevents doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.

AB - Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, a zebrafish model of doxorubicin-induced cardiomyopathy was previously established for small-molecule screening. Using this model, several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish and in mouse models have previously been identified. In this study, exploration of doxorubicin cardiotoxicity is expanded by screening 2271 small molecules from a proprietary, target-annotated tool compound collection. It is found that 120 small molecules can prevent doxorubicin-induced cardiotoxicity, including 7 highly effective compounds. Of these, all seven exhibited inhibitory activity towards cytochrome P450 family 1 (CYP1). These results are consistent with previous findings, in which visnagin, a CYP1 inhibitor, also prevents doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.

KW - Animals

KW - Animals, Genetically Modified

KW - Cardiomyopathies/chemically induced

KW - Cytochrome P450 Family 1/antagonists & inhibitors

KW - Disease Models, Animal

KW - Doxorubicin/toxicity

KW - Heart Failure

KW - Mutagenesis

KW - Phenotype

KW - Small Molecule Libraries/chemistry

KW - Structure-Activity Relationship

KW - Zebrafish

KW - Zebrafish Proteins/antagonists & inhibitors

U2 - 10.1002/cbic.201900741

DO - 10.1002/cbic.201900741

M3 - SCORING: Journal article

C2 - 32003101

VL - 21

SP - 1905

EP - 1910

JO - CHEMBIOCHEM

JF - CHEMBIOCHEM

SN - 1439-4227

IS - 13

ER -