Endoplasmic reticulum stress contributes to arsenic trioxide‐induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells |
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| Authors: | Yih‐An King Yu‐Jen Chiu Hao‐Ping Chen Daih‐Huang Kuo Chi‐Cheng Lu Jai‐Sing Yang |
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| Affiliation: | 1. Department of Dermatology, Taipei Medical University Hospital, Taipei, Taiwan;2. Division of Reconstructive and Plastic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan;3. Department of Biochemistry, Tzu Chi University, Hualien, Taiwan;4. Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung, Taiwan;5. Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan;6. Bracco Pharmaceutical Corp. Ltd., Taipei, Taiwan |
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| Abstract: | Arsenic trioxide is an old drug and has been used for a long time in traditional Chinese and Western medicines. However, the cancer treatment of arsenic trioxide has heart and vascular toxicity. The cytotoxic effects of arsenic trioxide and its molecular mechanism in human umbilical mesenchymal stem cells (HUMSC) and human bone marrow‐derived mesenchymal stem cells (HMSC‐bm) were investigated in this study. Our results showed that arsenic trioxide significantly reduced the viability of HUMSC and HMSC‐bm in a concentration‐ and time‐dependent manner. Arsenic trioxide is able to induce apoptotic cell death in HUMSC and HMSC‐bm, as shown from the results of morphological examination, flow cytometric analyses, DAPI staining and comet assay. The appearance of arsenic trioxide also led to an increase of intracellular free calcium (Ca2+) concentration and the disruption of mitochondrial membrane potential (ΔΨm). The caspase‐9 and caspase‐3 activities were time‐dependently increased in arsenic trioxide‐treated HUMSC and HMSC‐bm. In addition, the proteomic analysis and DNA microarray were carried out to investigate the expression level changes of genes and proteins affected by arsenic trioxide treatment in HUMSC. Our results suggest that arsenic trioxide induces a prompt induction of ER stress and mitochondria‐modulated apoptosis in HUMSC and HMSC‐bm. A framework was proposed for the effect of arsenic trioxide cytotoxicity by targeting ER stress. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 314–328, 2016. |
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| Keywords: | arsenic trioxide apoptosis ER stress mitochondria mesenchymal stem cells |
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