Combined Inhibition of Notch Signaling and Bcl-2/Bcl-xL Results in Synergistic Antimyeloma Effect

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 g-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. Mol Cancer Ther; 9(12); 3200-9. (C) 2010 AACR.