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Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenström's Macroglobulinemia

Authors' Affiliations: ¹ Bing Center for Waldenström's Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts; ² Unit of Blood Diseases and Cell Therapies, University of Brescia Medical School, Brescia, Italy; and ³ Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy

Requests for reprints: Aldo M. Roccaro, Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Mayer Building, M548 Boston, MA 02215. Phone: 617-582-8235; E-mail: aldo_roccaro{at}dfci.harvard.edu.

Purpose: 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.

Experimental Design: 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: 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-NH₂-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.

Conclusion: Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.