title: Combined inhibition of Notch signaling and Bcl-2/Bcl-xL results in synergistic antimyeloma effect.
abstract: Signaling through the receptor/transcriptional regulator Notch plays an important role in tumor cell survival. Recent studies have demonstrated that pharmacological inhibition of the Notch pathway with γ-secretase inhibitor (GSI) induces apoptosis of multiple myeloma (MM) cells via upregulation of the proapoptotic protein Noxa. ABT-737, a novel BH3 mimetic, was shown to block Bcl-2 and Bcl-xL and induce MM cell apoptosis. Here, we investigated whether the inhibition of Notch signaling could enhance the proapoptotic effect of ABT-737. The antimyeloma effect of ABT-737 on MM cell lines or primary cells was substantially increased by the addition of Notch inhibitor. The synergistic effect of the GSI+ABT-737 combination was mediated by activation of Bak and Bax and release of cytochrome c. While toxic for MM cells, the combination of GSI and ABT-737 did not affect survival of peripheral blood mononuclear cells isolated from healthy donors. In vivo experiments using xenograft and SCID-hu models of MM demonstrated a significant antitumor effect of the GSI/ABT-737 combination as compared to the effect of Notch or Bcl-2/Bcl-xL inhibitors alone. Thus, this drug combination may be therapeutically beneficial for patients with MM.
authors.affiliation: H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Clifton
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: William S
authors.initials: WS
authors.lastname: Dalton
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
authors.forename: Yulia
authors.initials: Y
authors.lastname: Nefedova
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D009842:Oligopeptides; D010879:Piperazines; D051880:Receptors, Notch; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D053829:Amyloid Precursor Protein Secretases