title: Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like Cells.
abstract: BACKGROUND
  Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity.
  
  
  METHODS
  We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit.
  
  
  RESULTS
  MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors.
  
  
  CONCLUSIONS
  These results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.|Department of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Chen
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chiao-Hui
authors.initials: CH
authors.lastname: Tu
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Salazar
authors.affiliation: Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Yun
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: Department of Public Health, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.|Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shiang-Fu
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Department of Public Health, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Hsieh
authors.affiliation: Department of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tai-Ngar
authors.initials: TN
authors.lastname: Lui
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002945:Cisplatin / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009842:Oligopeptides / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C522798:LBW242; C574246:LCL161; D009842:Oligopeptides; D013844:Thiazoles; D014750:Vincristine; D053148:Caspase 3; D053179:Caspase 7; D002945:Cisplatin