Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model
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Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model. / Lam, Pui-Ying; Kutchukian, Peter; Anand, Rajan; Imbriglio, Jason; Andrews, Christine; 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.
in: CHEMBIOCHEM, Jahrgang 21, Nr. 13, 01.07.2020, S. 1905-1910.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -