Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenström's macroglobulinemia.
OBJECTIVE
Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated.


METHODS
We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM.


RESULTS
A schematic image illustrating the location and expression of the aurora kinases A, B, and C during mitosis. Resveratrol inhibited proliferation and induced cytotoxicity against WM cells, IgM-secreting cells, as well as primary WM cells, without affecting peripheral blood mononuclear cells; down-regulated Akt, extracellular signal-regulated kinase mitogen-activated protein kinases, and Wnt signaling pathways, as well as Akt activity; induced cell cycle arrest and apoptosis; and triggered c-Jun-NH(2)-terminal-kinase activation, followed by the activation of intrinsic and extrinsic caspase pathways. Lastly, adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with dexamethasone, fludarabine, and bortezomib.


CONCLUSIONS
Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.
Roccaro
Aldo M
AM
Bing Center for Waldenström's Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. aldo_roccaro@dfci.harvard.edu
Leleu
Xavier
X
Sacco
Antonio
A
Moreau
Anne-Sophie
AS
Hatjiharissi
Evdoxia
E
Jia
Xiaoying
X
Xu
Lian
L
Ciccarelli
Bryan
B
Patterson
Christopher J
CJ
Ngo
Hai T
HT
Russo
Domenico
D
Vacca
Angelo
A
Dammacco
Franco
F
Anderson
Kenneth C
KC
Ghobrial
Irene M
IM
Treon
Steven P
SP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011719:Pyrazines / Q000008:administration & dosage; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051820:TCF Transcription Factors / Q000235:genetics / Q000502:physiology; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051176:beta Catenin / Q000235:genetics / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D011719:Pyrazines; D013267:Stilbenes; D051820:TCF Transcription Factors; D051176:beta Catenin; D000069286:Bortezomib; D003907:Dexamethasone; D014740:Vidarabine; C024352:fludarabine; D000077185:Resveratrol