Doxorubicin caused apoptosis of mesenchymal stem cells via p38, JNK and p53 pathway.
OBJECTIVE
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 apoptosis 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 Bcl-2 protein was reduced in doxorubicin-treated BMSCs. At last, ELISA assay showed that doxorubicin treatment reduced the VEGF and IGF-1 released by BMSCs.


CONCLUSIONS
Taken together, doxorubicin caused BMSCs apoptosis associated with p38, JNK and p53 pathways.
Department of Pharmacology, State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, China.
Fan
F
Yang
Hongyang
H
Chen
Yanju
Y
Liu
Kun
K
Yin
Yang
Y
Wang
Xingda
X
Li
Guohui
G
Wang
Siyue
S
Wang
Xueying
X
Tan
Chaoqian
C
Xu
Yanjie
Y
Lu
Benzhi
B
Cai
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases