title: A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.
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.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Rai
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Kitae E
authors.initials: KE
authors.lastname: Park
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Mesut
authors.initials: M
authors.lastname: Eren
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Tohoku University, Miyagi, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Wilsbacher
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D066126:Cardiotoxicity / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D058258:Serpin E2 / Q000037:antagonists & inhibitors*; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D010879:Piperazines; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C000623364:TM5441; D062366:para-Aminobenzoates; D004317:Doxorubicin
keywords: Doxorubicin; cardiomyocytes; cellular senescence; endothelial cells; fibroblasts