Oncotarget

Research Papers: Gerotarget (Focus on Aging):

A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence

Asish K. Ghosh, Rahul Rai, Kitae E. Park, Mesut Eren, Toshio Miyata, Lisa D. Wilsbacher and Douglas E. Vaughan _

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Oncotarget. 2016; 7:72443-72457. https://doi.org/10.18632/oncotarget.12494

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Abstract

Asish K. Ghosh1, Rahul Rai1, Kitae E. Park1, Mesut Eren1, Toshio Miyata2, Lisa D. Wilsbacher1 and Douglas E. Vaughan1

1 Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

2 United Centers for Advanced Research and Translational Medicine, Tohoku University, Miyagi, Japan

Correspondence to:

Douglas E. Vaughan, email:

Asish K. Ghosh, email:

Keywords: cellular senescence, doxorubicin, cardiomyocytes, fibroblasts, endothelial cells, Gerotarget

Received: June 15, 2016 Accepted: September 29, 2016 Published: October 06, 2016

Abstract

Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile.


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