Targeting NF-kappaB in Waldenstrom macroglobulinemia.
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.
Leleu
Xavier
X
Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
Eeckhoute
Jérôme
J
Jia
Xiaoying
X
Roccaro
Aldo M
AM
Moreau
Anne-Sophie
AS
Farag
Mena
M
Sacco
Antonio
A
Ngo
Hai T
HT
Runnels
Judith
J
Melhem
Molly R
MR
Burwick
Nicolas
N
Azab
Abdelkareem
A
Azab
Feda
F
Hunter
Zachary
Z
Hatjiharissi
Evdoxia
E
Carrasco
Daniel R
DR
Treon
Steven P
SP
Witzig
Thomas E
TE
Hideshima
Teru
T
Brown
Myles
M
Anderson
Kenneth C
KC
Ghobrial
Irene M
IM
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
D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D010767:Phosphorylcholine; C105905:perifosine; D000069286:Bortezomib