Citations 1
Targeting NF-κB in Waldenstrom macroglobulinemia
Leleu, Xavier , Eeckhoute, Jérôme , Jia, Xiaoying , Roccaro, Aldo M. , Moreau, Anne-Sophie, Sacco, Antonio , Ngo, Hai T., Runnels, Judith, Melhem, Molly, Burwick, Nicolas, Azab, Abdelkareem, Azab, Feda, Hunter, Zachary R. , Hatjiharissi, Evdoxia , Carrasco, Daniel R., Hideshima, Teru , Brown, Myles , Farag, Mena S. , Treon, Steven P. , Witzig, Thomas E. , Anderson, Kenneth C. , Ghobrial, Irene M. , Roccaro, Aldo M , Hunter, Zachary R , Brown, Myles
Blood | March 12, 2008 | Volume: 111 | Issue: 10 | Pages: 5068-5077
Abstract The nuclear factor-κB (NF-κB) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-κB pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-κB activity. We demonstrated that perifosine and bortezomib both targeted NF-κB through its recruitment to the promoter of its target gene IκB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-κB pathway.