Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia |
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Authors: | Roccaro Aldo M Leleu Xavier Sacco Antonio Jia Xiaoying Melhem Molly Moreau Anne-Sophie Ngo Hai T Runnels Judith Azab Abdelkareem Azab Feda Burwick Nicholas Farag Mena Treon Steven P Palladino Michael A Hideshima Teru Chauhan Dharminder Anderson Kenneth C Ghobrial Irene M |
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Institution: | 1 Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA; 2 Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy; 3 Unit of Blood Diseases and Cell Therapies, University of Brescia Medical School, Brescia, Italy; and 4 Nereus Pharmaceuticals, San Diego, CA |
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Abstract: | Waldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF- B and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF- B pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052–induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM. |
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