Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model. Chembiochem 2020 Jul 01;21(13):1905-1910
Date
02/01/2020Pubmed ID
32003101Pubmed Central ID
PMC7500981DOI
10.1002/cbic.201900741Scopus ID
2-s2.0-85080951472 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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.
Author List
Lam PY, Kutchukian P, Anand R, Imbriglio J, Andrews C, Padilla H, Vohra A, Lane S, Parker DL Jr, Cornella Taracido I, Johns DG, Beerens M, MacRae CA, Caldwell JP, Sorota S, Asnani A, Peterson RTAuthor
Pui Ying Lam PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Genetically Modified
Cardiomyopathies
Cytochrome P450 Family 1
Disease Models, Animal
Doxorubicin
Heart Failure
Mutagenesis
Phenotype
Small Molecule Libraries
Structure-Activity Relationship
Zebrafish
Zebrafish Proteins
