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.
Highlights
Senescence is a cellular process by which cells stop proliferation irreversibly and undergo morphological changes due to expression of high levels of cell cycle inhibitors and sub-set of genes whose products are involved in senescence [1, 2]
Cultured cells were pretreated with TM5441 for 1 day followed by treatment with Doxorubicin for 4 days
TM5441 pretreated cells are significantly protected from Doxorubicin-induced cellular senescence as evidenced by the decrease in SA-β-gal positive cells in cultures cotreated with Doxorubicin and TM5441 (Figure 1A-1D lower panels; see Supplemental Figure 1A-1D)
Summary
Senescence is a cellular process by which cells stop proliferation irreversibly and undergo morphological changes due to expression of high levels of cell cycle inhibitors and sub-set of genes whose products are involved in senescence [1, 2]. Senescence can be induced in cultured cells using a wide variety of senescence-inducing stimuli including culture shock stress, high serum-induced cellular stress, H2O2 and anticancer-drug-induced stresses Most of these stresses contribute to generate reactive oxygen species (ROS), leading to telomere erosion and DNA damage [1, 2, 5, 6]. The present study was undertaken to test the hypothesis that pharmacological inhibition of PAI1 activity may protect normal cells from stress-induced and aging-associated cellular senescence. It is known that PAI-1 is an important regulator of cellular senescence and importantly PAI-1 is induced by Doxorubicin in vitro in cultured cells and in cancer patients undergoing Doxorubicin treatment [11, 20] These important findings lead us to test the hypothesis that pharmacological inhibition of cellular PAI-1 activity using a specific inhibitor protects cells from doxorubicin-induced senescence, and its associated complications. PAI-1 is a druggable target and pharmacological inhibition of elevated PAI-1 levels may protect healthy cells from stress-induced premature senescence and accelerated aging process
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