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Mol Cancer Ther. 2010 Dec;9(12):3200-9. doi: 10.1158/1535-7163.MCT-10-0372.

Combined inhibition of Notch signaling and Bcl-2/Bcl-xL results in synergistic antimyeloma effect.

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1
H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

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.

PMID:
21159606
PMCID:
PMC3058809
DOI:
10.1158/1535-7163.MCT-10-0372
[Indexed for MEDLINE]
Free PMC Article
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