Targeting OCT3 attenuates doxorubicin-induced cardiac injury.

Abstract

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.

• Authors: Kevin M Huang, Megan Zavorka Thomas, Tarek Magdy, Eric D Eisenmann, Muhammad Erfan Uddin, Duncan F DiGiacomo, Alexander Pan, Markus Keiser, Marcus Otter, Sherry H Xia, Yang Li, Yan Jin, Qiang Fu, Alice A Gibson, Ingrid M Bonilla, Cynthia A Carnes, Kara N Corps, Vincenzo Coppola, Sakima A Smith, Daniel Addison, Anne T Nies, Ralf Bundschuh, Taosheng Chen, Maryam B Lustberg, Joanne Wang, Stefan Oswald, Moray J Campbell, Pearlly S Yan, Sharyn D Baker, Shuiying Hu, Paul W Burridge, Alex Sparreboom
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 5 (02 02 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33495337 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Organic Anion Transporters, Sodium-Independent
• Pyrimidines
• organic anion transport protein 3
• Doxorubicin
• nilotinib

Topics

• Animals
• Child
• Doxorubicin (adverse effects)
• Gene Expression Regulation
• Heart Injuries (chemically induced, drug therapy, physiopathology)
• Humans
• Mice
• Molecular Targeted Therapy
• Myocytes, Cardiac (metabolism)
• Neoplasms (drug therapy, metabolism)
• Organic Anion Transporters, Sodium-Independent (deficiency, metabolism)
• Pyrimidines (pharmacology, therapeutic use)
• Sequence Analysis, RNA