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

Autor: Lam PY; Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT, 84112, USA., Kutchukian P; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA, 02115, USA., Anand R; Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA., Imbriglio J; Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA., Andrews C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA, 02115, USA., Padilla H; Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT, 84112, USA., Vohra A; CardioVascular Institute, Beth Israel Deaconess Medical Center, and, Harvard Medical School, Boston, MA, 02115, USA., Lane S; CardioVascular Institute, Beth Israel Deaconess Medical Center, and, Harvard Medical School, Boston, MA, 02115, USA., Parker DL Jr; Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA., Cornella Taracido I; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA, 02115, USA., Johns DG; Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA., Beerens M; Department of Cardiovascular Medicine, Genetics and Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., MacRae CA; Department of Cardiovascular Medicine, Genetics and Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Caldwell JP; Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA., Sorota S; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA, 02115, USA., Asnani A; CardioVascular Institute, Beth Israel Deaconess Medical Center, and, Harvard Medical School, Boston, MA, 02115, USA., Peterson RT; Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT, 84112, USA.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2020 Jul 01; Vol. 21 (13), pp. 1905-1910. Date of Electronic Publication: 2020 Mar 06.
DOI: 10.1002/cbic.201900741
Abstrakt: 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.
(© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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