Inhibition of p38 MAPK Reduces Ionizing Radiation (IR)-Induced Hematopoietic Suppression by Preventing Hematopoietic Stem/Progenitor Cell Senescence.

Abstract

Bone marrow (BM) suppression is the most common dose-limiting side effect of conventional cancer therapy, particularly with certain alkylating agents and/or ionizing radiation (IR). It has been shown that p38 mitogen-activated protein kinase (p38 MAPK) plays a critical role in regulation of hematopoiesis and its activation mediates IR- and chemotherapy-induced cell injury and oxidative stress-induced hematopoietic stem cell (HSC) exhaustion. Therefore, we examined the role of p38 MAPK in radiation-induced BM injury. First, we monitored the activation of p38 MAPK in BM hematopoietic cells at different time after exposure to IR using our well-established long-term BM cell culture (LTBMC) model system. The activation of p38 MAPK was detected within 24 hours after BM hematopoietic cells were exposed to 4 Gy IR and this activation sustained up to 5 weeks after radiation. Inhibition of p38 MAPK activity with a p38 MAPK specific inhibitor (SB202190) attenuated IR-induced suppression of the hematopoietic function of BM hematopoietic cells in an in vitro colony forming cell (CFC) assay. Moreover, the number of hematopoietic progenitor cells produced by SB202190-treated BM cells was significantly greater than that by the cells without SB202190 treatment after exposure to IR and followed by a five-week LTBMC. Interestingly, p38 MAPK inhibition showed no effect on IR-induced apoptosis in both HSCs and hematopoietic progenitor cells (HPCs), whereas the radioprotection effect of SB202190 was associated with a significantly reduction of p16INK4a expression and senescence-associated β-galactosidase (SA-β-Gal) activity in irradiated BM cells after five weeks of LTBMC. These findings suggest that activation of p38 MAPK may mediate IR-induced hematopoietic suppression by induction of hematopoietic stem/progenitor cell senescence and pharmacological inhibition of the p38 MAPK pathway may have the potential to be developed as an innovatively therapeutic strategy to ameliorate IR- and chemotherapy-induced BM toxicity.