title: Targeting NF-kappaB in Waldenstrom macroglobulinemia.
abstract: The nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB activity. We demonstrated that perifosine and bortezomib both targeted NF-kappaB through its recruitment to the promoter of its target gene IkappaB 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-kappaB pathway.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Jérôme
authors.initials: J
authors.lastname: Eeckhoute
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jia
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Moreau
authors.forename: Mena
authors.initials: M
authors.lastname: Farag
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Judith
authors.initials: J
authors.lastname: Runnels
authors.forename: Molly R
authors.initials: MR
authors.lastname: Melhem
authors.forename: Nicolas
authors.initials: N
authors.lastname: Burwick
authors.forename: Abdelkareem
authors.initials: A
authors.lastname: Azab
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hunter
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Hatjiharissi
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carrasco
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000473:pathology
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D010767:Phosphorylcholine; C105905:perifosine; D000069286:Bortezomib