The HMG-CoA inhibitor, simvastatin, triggers in vitro anti-tumour effect and decreases IgM secretion in Waldenstrom macroglobulinaemia.
Waldenstrom macroglobulinaemia (WM) is an incurable lymphoplasmacytic lymphoma with secretion of serum monoclonal immunoglobulin M (IgM). We previously showed that patients receiving cholesterol-lowering statins, had the lowest IgM value in a large cohort of patients with WM. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, induced inhibition of proliferation, cytotoxic effect and apoptosis in IgM secreting cell lines as well as in primary CD19(+) WM cells. Interestingly, those effects were reversed by addition of mevalonate and geranylgeranylpyrophosphate, demonstrating that simvastatin inhibited cell growth, survival and IgM secretion on BCWM.1 WM cells by inhibition of geranylgeranylated proteins. Furthermore, simvastatin overcame tumour cell growth induced by co-culture of WM cells with bone-marrow stromal cells. Simvastatin also decreased IgM secretion by BCWM.1 cells at an early time-point that had not affected cell survival. Simvastatin-induced cytotoxicity was preceded by a decrease in Akt (protein kinase B, PKB) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathways at 18 h. In addition, simvastatin induced an increase in stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) MAPK followed by caspase-8, -9, -3 and poly(ADP-ribose) polymerase (PARP) cleavages at 18 h, leading to apoptosis. Furthermore, simvastatin enhanced the cytotoxicity induced by bortezomib, fludarabine and dexamethasone. Our studies therefore support our earlier observation of statin-mediated anti-WM activity and provide the framework for future clinical trials testing simvastatin in WM.
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA.
Anne-Sophie
AS
Moreau
Xiaoying
X
Jia
Christopher J
CJ
Patterson
Aldo M
AM
Roccaro
Lian
L
Xu
Antonio
A
Sacco
Kelly
K
O'Connor
Jacob
J
Soumerai
Hai T
HT
Ngo
Evdoxia
E
Hatjiharissi
Zachary R
ZR
Hunter
Bryan
B
Ciccarelli
Robert
R
Manning
Irene M
IM
Ghobrial
Xavier
X
Leleu
Steven P
SP
Treon
D017209:Apoptosis / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007075:Immunoglobulin M / Q000378:metabolism; D066298:In Vitro Techniques; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000201:enzymology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007075:Immunoglobulin M; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases