title: Cytotoxicity, drug combinability, and biological correlates of ABT-737 against acute lymphoblastic leukemia cells with MLL rearrangement.
abstract: BACKGROUND
  ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 to induce apoptosis in malignant cells and has shown promise as an effective anti-leukemic agent in pediatric preclinical tests. This study focuses on the effects of ABT-737 on leukemia cells with MLL rearrangement and identifies some of the biological correlates of its activity.
  
  
  METHODS
  Cells were cultured in the presence of increasing concentrations of ABT-737 alone or in combination with other agents. After 4 days in culture, cell growth inhibition was measured by Alamar blue assay. The expression and activation of potential intracellular targets of ABT-737 activity were determined by Western blot analysis.
  
  
  RESULTS
  Significant Bcl-2 expression was detected in all infant leukemia cells investigated. ABT-737 induced cell death in all cell lines studied although the IC(50) values differed somewhat between cell lines. Western blot analysis identified the effects of ABT-737 on survival and apoptosis-regulatory proteins PARP, caspase-8, and cytochrome-c. Drug combination studies indicated synergy with distinct anti-neoplastic agents, including the multi-tyrosine kinase inhibitor sunitinib. This effective drug synergy appears to be mediated by the combined inhibition of Bcl-2 and intracellular signaling pathways.
  
  
  CONCLUSIONS
  We describe the in vitro studies to demonstrate the activity and drug combinability of ABT-737 against MLL rearranged leukemia cells. In addition, identification of the molecular changes that occur in the presence of ABT-737 provides information regarding effective target validation and target modulation analyses in future clinical trials.
authors.affiliation: Hughes' Children's Cancer Research Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Jayanthan
authors.forename: Andrea
authors.initials: A
authors.lastname: Incoronato
authors.forename: Anjali
authors.initials: A
authors.lastname: Singh
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackmore
authors.forename: Delphine
authors.initials: D
authors.lastname: Bernoux
authors.forename: Victor
authors.initials: V
authors.lastname: Lewis
authors.forename: Ronald
authors.initials: R
authors.lastname: Stam
authors.forename: James A
authors.initials: JA
authors.lastname: Whitlock
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004338:Drug Combinations; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004338:Drug Combinations; C497422:KMT2A protein, human; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051788:Myeloid-Lymphoid Leukemia Protein; D045304:Cytochromes c; D011495:Histone-Lysine N-Methyltransferase; D011065:Poly(ADP-ribose) Polymerases; D053181:Caspase 8