Zerumbone Abolishes RANKL-Induced NF-B Activation, Inhibits Osteoclastogenesis, and Suppresses Human Breast Cancer–Induced Bone Loss in Athymic Nude Mice

¹Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ²Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan; and ³Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas

^* To whom correspondence should be addressed. E-mail: aggarwal{at}mdanderson.org.

	Abstract

Receptor activator of nuclear factor-B (NF-B) ligand (RANKL) has emerged as a major mediator of bone resorption, commonly associated with cancer and other chronic inflammatory diseases. Inhibitors of RANKL signaling thus have potential in preventing bone loss. In the present report, the potential of zerumbone, a sesquiterpene derived from subtropical ginger, to modulate osteoclastogenesis induced by RANKL and breast cancer was examined. We found that zerumbone inhibited RANKL-induced NF-B activation in mouse monocyte, an osteoclast precursor cell, through inhibition of activation of IB kinase, IB phosphorylation, and IB degradation. Zerumbone also suppressed RANKL-induced differentiation of these cells to osteoclasts. This sesquiterpene also inhibited the osteoclast formation induced by human breast tumor cells and by multiple myeloma cells. Finally, we examined whether zerumbone could prevent human breast cancer–induced bone loss in animals. We found that zerumbone decreased osteolysis in a dose-dependent manner in MDA-MB-231 breast cancer tumor-bearing athymic nude mice. These results indicate that zerumbone is an effective blocker of RANKL-induced NF-B activation and of osteoclastogenesis induced by RANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss. [Cancer Res 2009;69(4):1477–84]

Key Words: zerumbone, NF-B, RANKL, osteoclastogenesis

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