标题：Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma
作者：Chen F.; Pisklakova A.; Li M.; Baz R.; Sullivan D.M.; Nefedova Y.
作者机构：[Chen, F] H. Lee Moffitt Cancer Center, Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, United States, Department of Hematology, Qilu Hospital 更多
通讯作者地址：Nefedova, Y.; H. Lee Moffitt Cancer Center, Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, United States; 电子邮件: firstname.lastname@example.org 更多
关键词：Bortezomib; Gamma-secretase inhibitor; Multiple myeloma; Notch inhibitor
摘要：Background Targeting of Notch signaling with γ-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 inMMcells 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. © International Society for Cellular Oncology 2011.