A small molecule inhibitor of PAI-1 protects against Doxorubicin-induced cellular senescence: molecular basis

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)72443-72457
Number of pages15
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 2016 Oct 6

Keywords

  • Cardiomyocytes
  • Cellular senescence
  • Doxorubicin
  • Endothelial cells
  • Fibroblasts

ASJC Scopus subject areas

  • Oncology

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