title: Inhibition of Bcl-2 family members sensitises soft tissue leiomyosarcomas to chemotherapy.
abstract: Leiomyosarcoma is an aggressive soft tissue sarcoma with a 5-year survival rate of 15 to 60%. Treatment options for inoperable or metastatic patients are limited owing to frequent resistance of tumours to chemotherapy and radiation. In this study, we hypothesised that antiapoptotic Bcl-2 family proteins might contribute to leiomyosarcoma chemoresistance and therefore inhibition of Bcl-2 family proteins might sensitise leiomyosarcomas to conventional chemotherapy.
  
  
  
  Expression of the Bcl-2 family proteins Bcl-xL, Bcl-w and Bcl-2 was investigated using immunohistochemistry on a tissue microarray containing 43 leiomyosarcomas. Furthermore, we investigated whether ABT-737, a potent BH3 mimetic, sensitises leiomyosarcoma cells to doxorubicin treatment in vitro.
  
  
  
  Seventy-seven per cent, 84% and 42% of leiomyosarcomas demonstrated high expression of Bcl-2, Bcl-xL and Bcl-w, respectively. Single-agent treatment with ABT-737 resulted in a minor reduction of cell viability. However, combination treatment of ABT-737 and doxorubicin revealed synergism in all four cell lines, by inducing apoptosis.
  
  
  
  In conclusion, Bcl-2 family proteins contribute to soft tissue leiomyosarcoma chemoresistance. Antiapoptotic proteins are highly expressed in leiomyosarcoma of soft tissue, and inhibition of these proteins using a BH3 mimetic increases leiomyosarcoma sensitivity to doxorubicin.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Marieke A
authors.initials: MA
authors.lastname: de Graaff
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Marije A J
authors.initials: MA
authors.lastname: de Rooij
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Brendy E W M
authors.initials: BE
authors.lastname: van den Akker
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Molecular Pathology, Institut Bergonie, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Chibon
authors.affiliation: Department of Molecular Pathology, Institut Bergonie, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Marino-Enriquez
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D012186:Retroperitoneal Neoplasms / Q000556:secondary; D012983:Soft Tissue Neoplasms / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000473:pathology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D001713:Biphenyl Compounds; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; D004317:Doxorubicin