Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma

Background Targeting of Notch signaling with gamma-secretase inhibitors (GSIs) has been considered a promising strategy for the treatment of hematological malignancies including multiple myeloma (MM). Here we investigated whether the cytotoxic effect of bortezomib, an agent commonly used in MM, could be enhanced by the addition of a GSI. Methods MM cells were treated with GSI, bortezomib or the combination thereof. Apoptosis of MM cells, proteasome activity and Notch signaling activation were determined. The effect of the drug combination was also evaluated in MM cells transfected with the active domain of Notch-1. Results Using MM cell lines and primary MM cells isolated from the bone marrow of patients with MM we found a strong synergistic effect of bortezomib in combination with one of the GSIs studied. We next investigated the mechanism underlying this synergistic effect and determined that the effect of the drug combination was mainly dependent on the ability of the selected GSI to inhibit proteasome activity in MM cells. Conclusion Our study demonstrates that selected GSIs that inhibit proteasome activity may be successfully used in combination with bortezomib enhancing its anti-MM effect.