Zerumbone abolishes RANKL-induced NF-kappaB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice

Cancer Res. 2009 Feb 15;69(4):1477-84. doi: 10.1158/0008-5472.CAN-08-3249. Epub 2009 Feb 3.


Receptor activator of nuclear factor-kappaB (NF-kappaB) 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-kappaB activation in mouse monocyte, an osteoclast precursor cell, through inhibition of activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, and IkappaBalpha 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-kappaB activation and of osteoclastogenesis induced by RANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss.

Publication types

  • Research Support, N.I.H., Extramural
  • Retracted Publication

MeSH terms

  • Animals
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control*
  • Breast Neoplasms / complications*
  • Cell Differentiation / drug effects*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism*
  • Osteogenesis / drug effects*
  • Osteoporosis / drug therapy
  • Osteoporosis / prevention & control*
  • RANK Ligand / drug effects
  • RANK Ligand / genetics*
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sesquiterpenes / therapeutic use*


  • NF-kappa B
  • RANK Ligand
  • RNA, Messenger
  • RNA, Neoplasm
  • Sesquiterpenes
  • zerumbone