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

// Asish K. Ghosh 1 , Rahul Rai 1 , Kitae E. Park 1 , Mesut Eren 1 , Toshio Miyata 2 , Lisa D. Wilsbacher 1 and Douglas E. Vaughan 1 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.