title: Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells.
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 (Ca(2+) ) 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.
authors.affiliation: Department of Dermatology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Yih-An
authors.initials: YA
authors.lastname: King
authors.affiliation: Division of Reconstructive and Plastic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chiu
authors.affiliation: Department of Biochemistry, Tzu Chi University, Hualien, Taiwan.
authors.forename: Hao-Ping
authors.initials: HP
authors.lastname: Chen
authors.affiliation: Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung, Taiwan.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Bracco Pharmaceutical Corp. Ltd., Taipei, Taiwan.
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D020543:Proteome / Q000032:analysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001152:Arsenicals; D010087:Oxides; D020543:Proteome; D053148:Caspase 3; D053453:Caspase 9; D000077237:Arsenic Trioxide
keywords: ER stress; apoptosis; arsenic trioxide; mesenchymal stem cells; mitochondria