气候变化领域集成服务门户(CCPortal): Targeting OCT3 attenuates doxorubicin-induced cardiac injury

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DOI	10.1073/pnas.2020168118
	Targeting OCT3 attenuates doxorubicin-induced cardiac injury
	Huang K.M.; Thomas M.Z.; Magdy T.; Eisenmann E.D.; Uddin M.E.; DiGiacomo D.F.; Pan A.; Keiser M.; Otter M.; Xia S.H.; Li Y.; Jin Y.; Fu Q.; Gibson A.A.; Bonilla I.M.; Carnes C.A.; Corps K.N.; Coppola V.; Smith S.A.; Addison D.; Nies A.T.; Bundschuh R.; Chen T.; Lustberg M.B.; Wang J.; Oswald S.; Campbell M.J.; Yan P.S.; Baker S.D.; Hu S.; Burridge P.W.; Sparreboom A.
发表日期	2021
ISSN	00278424
卷号	118 期号:5
英文摘要	Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell–derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cardiotoxicity; Doxorubicin; S100 proteins; Slc22a3; Solute carriers
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180794
作者单位	Department of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, United States; Department of Pharmacology and Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Division of Hematology, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH 43210, United States; Department of Pharmacology, University Medicine Greifswald, Greifswald, 17489, Germany; Department of Physiology and Cell Biology, College of Medicine, Ohio State University, Columbus, OH 43210, United States; Outcomes and Translational Sciences, College of Pharmacy, Ohio State University, Columbus, OH 43210, United States; Comparative Pathology and Digital Imaging Shared Resource, College of Veterinary Medicine, Ohio State University, Columbus, OH 43210, United States; Department of Cancer Biology and Genetics, College of Medicine, Ohio State University, Columbus, OH...
推荐引用方式 GB/T 7714	Huang K.M.,Thomas M.Z.,Magdy T.,et al. Targeting OCT3 attenuates doxorubicin-induced cardiac injury[J],2021,118(5).
APA	Huang K.M..,Thomas M.Z..,Magdy T..,Eisenmann E.D..,Uddin M.E..,...&Sparreboom A..(2021).Targeting OCT3 attenuates doxorubicin-induced cardiac injury.Proceedings of the National Academy of Sciences of the United States of America,118(5).
MLA	Huang K.M.,et al."Targeting OCT3 attenuates doxorubicin-induced cardiac injury".Proceedings of the National Academy of Sciences of the United States of America 118.5(2021).