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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4752-4763.
Prepublished online as a Blood First Edition Paper on March 3, 2008; DOI 10.1182/blood-2007-11-120972.
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Submitted November 2, 2007
Accepted February 16, 2008
Dual targeting of the proteasome regulates survival and homing in Waldenstrom's Macroglobulinemia
Aldo M Roccaro, Xavier Leleu, Antonio Sacco, Xiaoying Jia, Molly Melhem, Anne-Sophie Moreau, Hai T Ngo, Judith Runnels, Abdelkareem Azab, Feda Azab, Nicholas Burwick, Mena Farag, Steven P Treon, Michael A Palladino, Teru Hideshima, Dharminder Chauhan, Kenneth C Anderson, and Irene M Ghobrial*
Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, United States
Nereus Pharmaceuticals, San Diego, CA, United States
* Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu.
Waldenstrom's Macroglobulinemia (WM) is an incurable low grade B-cell lymphoma characterized by high protein turnover. We dissected the biological role of the proteasome in WM using two 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, -9 and PARP cleavage. These two agents inhibited the canonical and non-canonical NF-B pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspase-like and trypsin-like 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 IL-6 in a co-culture in vitro system. Theses studies enhance our understanding of the biological 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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