Doxorubicin Caused Apoptosis of Mesenchymal Stem Cells via p38, JNK and p53 Pathway

Background/Aims: Doxorubicin is a widely used chemotherapeutic agent, but its clinical use is restricted because of a high risk of cardiotoxicity. Bone marrow-derived mesenchymal stem cells (BMSCs) may repair ischaemically damaged myocardium through transdifferentiation and paracrine action. The aim of this study is to investigate if doxorubicin causes the apoptosis of BMSCs and in turn impairs its healing ability. Methods: BMSCs were exposed to doxorubicin, and cell a poptosis was determined by western blot and stainings. Results: Doxorubicin reduced the survival ratio and caused the apoptosis of BMSCs, with the increase of intracellular ROS level and depolarization of mitochondrial membrane potential. The ROS scavenger NAC abrogated these consequences. Moreover, doxorubicin markedly activated phosphorylated ERK, p38 and JNK proteins in BMSCs. The specific inhibitors for p38 (SB203580) and JNK (SP600125) may abolish doxorubicin-induced apoptosis of BMSCs but the specific ERK inhibitor (PD98059) not, indicating p38 and JNK activation contribute to BMSCs apoptosis. Also, the phosphorylated and total p53 proteins were increased in doxorubicin-treated BMSCs. Proapoptotic cleaved caspases-3 was upregulated and antiapoptotic BcI-2 protein was reduced in doxorubicintreated BMSCs. At last, ELISA assay showed that doxorubicin treatment reduced the VEGF and IGF-1 released by BMSCs. Conclusion: Taken together, doxorubicin caused BMSCs apoptosis associated with p38, JNK and p53 pathways. Copyright 0 2013 S. Karger AG, Basel