title: Mechanisms underlying effect of the mycotoxin cytochalasin B on induction of cytotoxicity, modulation of cell cycle, Ca2+homeostasis and ROS production in human breast cells.
abstract: Cytochalasin B, a cell-permeable mycotoxin isolated from the fungus Phoma spp., shows a wide range of biological effects, among which its potent antitumor activity has raised great interests in different models. However, the cytotoxic activity of cytochalasin B and its underlying mechanisms have not been elucidated in breast cells. This study examined the effect of cytochalasin B on MCF 10A human breast epithelial cells and ZR-75-1 human breast cancer cells. Cytochalasin B (10-20μM) concentration-dependently induced cytotoxicity, cell cycle arrest, and [Ca2+]irises in ZR-75-1 cells but not in MCF 10A cells. In ZR-75-1 cells, cytochalasin B triggered G2/M phase arrest through the modulation of CDK1, cyclin B1, p53, p27 and p21 expressions. The Ca2+signal response induced by cytochalasin B was reduced by removing extracellular Ca2+and was inhibited by the store-operated Ca2+channel blocker 2-APB and SKF96365. In Ca2+-free medium, cytochalasin B induced Ca2+release through thapsigargin-sensitive endoplasmic reticulum stores. Moreover, cytochalasin B increased H2O2levels but reduced GSH levels. The apoptotic effects evoked by cytochalasin B were partially inhibited by prechelating cytosolic Ca2+with BAPTA-AM and the antioxidant NAC. Together, in ZR-75-1 cells but not in MCF 10A cells, cytochalasin B activated Ca2+-associated mitochondrial apoptotic pathways that involved G2/M phase arrest and ROS signaling. Furthermore, cytochalasin B induced [Ca2+]irises by releasing Ca2+from the endoplasmic reticulum and causing Ca2+influx through 2-APB or SKF96365-sensitive store-operated Ca2+entry. Our findings provide new insights into the possible application of cytochalasin B in human breast cancer therapy.
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan, ROC; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan, ROC.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: I-Shu
authors.initials: IS
authors.lastname: Chen
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan, ROC.
authors.forename: Ti
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Shu-Shong
authors.initials: SS
authors.lastname: Hsu
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC,. Electronic address: lianggoole67@gmail.com.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000188:drug therapy; D016203:CDC2 Protein Kinase; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003571:Cytochalasin B; D006861:Hydrogen Peroxide; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D002118:Calcium
keywords: Apoptosis; Ca(2+); Cell cycle; Cytochalasin B; Human breast cells; ROS