Low, sub-apoptotic doses of doxorubicin induced a senescence phenotype in endothelial progenitor cells, characterized by increased SA-β-gal activity and cytoplasmic p16INK4A accumulation, mediated antagonistically by p38 MAPK and JNK.
Does doxorubicin induce premature senescence in endothelial progenitor cells?
Low-dose doxorubicin induces premature senescence and impairs the migratory capacity of endothelial progenitor cells via p38 and JNK pathways, providing a potential mechanism for late-onset anthracycline cardiotoxicity.
Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs) exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16 INK4A localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16 INK4A , suggests that doxorubicin-induced p16 INK4A does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16 INK4A expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicintreated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity.
Spallarossa et al. (Mon,) conducted a other in Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Untreated cells was evaluated on Senescence (SA-β-gal activity) and apoptosis (ssDNA). Low, sub-apoptotic doses of doxorubicin induced a senescence phenotype in endothelial progenitor cells, characterized by increased SA-β-gal activity and cytoplasmic p16INK4A accumulation, mediated antagonistically by p38 MAPK and JNK.
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