title: BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models.
abstract: BACKGROUND
  Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells.
  
  
  METHODS
  Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model.
  
  
  RESULTS
  Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model.
  
  
  CONCLUSIONS
  BH3 mimetics represent a novel treatment modality for chondrosarcoma.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan t-morii@gb3.so-net.ne.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morii
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Ohtsuka
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mochizuki
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshiyama
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Aoyagi
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, U.S.A.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ichimura
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D049109:Cell Proliferation / Q000187:drug effects*; D002813:Chondrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D018716:Molecular Mimicry; D058990:Molecular Targeted Therapy; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C528561:navitoclax
keywords: BH3 mimetics; Bcl2; Chondrosarcoma; apoptosis