title: ABT-737 induces apoptosis in mantle cell lymphoma cells with a Bcl-2high/Mcl-1low profile and synergizes with other antineoplastic agents.
abstract: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737.
  
  
  
  Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy.
  
  
  
  MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD₅₀) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2(high)/Mcl-1(low) profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737-resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine.
  
  
  
  The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2(high)/Mcl-1(low) profile. In ABT-737-resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1-induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL.
authors.affiliation: INSERM UMR 892, Université de Nantes, Nantes, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Touzeau
authors.forename: Christelle
authors.initials: C
authors.lastname: Dousset
authors.forename: Linda
authors.initials: L
authors.lastname: Bodet
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Bougie
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonnaud
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: Catherine
authors.initials: C
authors.lastname: Pellat-Deceunynck
authors.forename: Martine
authors.initials: M
authors.lastname: Amiot
authors.forename: Steven
authors.initials: S
authors.lastname: Le Gouill
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein