title: The Bcl-2/Bcl-XL inhibitor ABT-737 promotes death of retinoblastoma cancer cells.
abstract: OBJECTIVE
  Retinoblastoma is a malignant tumor that usually develops in early childhood. During retinoblastoma spreading, RB1 gene inactivation is followed by additional genomic modifications which progressively lead to resistance of tumor cells to death. Drugs that act at downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. ABT-737, a BH3 mimetic molecule effective at the mitochondrial level, has been shown to induce apoptosis in different human tumoral cell lines as well as in primary patient-derived cells, and in a mouse xenograph model.
  
  
  METHODS
  In this report, we analyzed the pro-death effect of ABT-737 on two human retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the mouse photoreceptor cell line 661W.
  
  
  RESULTS
  We observed that ABT-737 was very effective as a single agent in inducing human WERI-Rb cells apoptosis without affecting the mouse 661W photoreceptor cells. However human Y79 cells were resistant to ABT-737, as a probable consequence of the absence of Bax. The high sensitivity of WERI-Rb to ABT-737 can be increased by downregulating Mcl-1 using the proteasome inhibitor MG-132. Preliminary analysis in primary mouse retinoblastoma tumoral cell lines predicts high sensitivity to ABT-737.
  
  
  CONCLUSIONS
  Our data suggest that ABT-737 or related compounds could be a highly effective drug in the treatment of some retinoblastomas.
authors.affiliation: Institute for Research in Ophthalmology, Sion, Switzerland. nathalie.allaman-pillet@irovision.ch
authors.forename: Nathalie
authors.initials: N
authors.lastname: Allaman-Pillet
authors.forename: Anne
authors.initials: A
authors.lastname: Oberson
authors.forename: Francis
authors.initials: F
authors.lastname: Munier
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019572:Retinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D012175:Retinoblastoma / Q000378:metabolism / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D051020:bcl-X Protein; D053148:Caspase 3; D053179:Caspase 7