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

Abstract

Receptor activator of nuclear factor-KB (NF-KB) 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-KB activation in mouse monocyte, an osteoclast precursor cell, through inhibition of activation of IKBA kinase, IKBA phosphorylation, and IKBA 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 tumorbearing athymic nude mice. These results indicate that zerumbone is an effective blocker of RANKL-induced NF-KB activation and of osteoclastogenesis induced by RANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss.

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

“…As the latter is a member in the TNF family of cytokines, agents that can suppress its signaling have been suggested to have therapeutic potential against inflammatory disorders. Aggarwal and co-workers reported that zerumbone can inhibit RANKL-induced NF-kB activation in mouse macrophages (RAW264.7 cells) in a dose-and time-dependent manner [63]. The compound inhibited RANKLinduced IkBa phosphorylation and degradation, IKK activation and osteoclastogenesis.…”

“…The process is mediated by osteoclast cells which are generated from hematopoietic cells by the action of several entities including the receptor activator of NF-kB (RANK) and its ligand RANKL [63]. As the latter is a member in the TNF family of cytokines, agents that can suppress its signaling have been suggested to have therapeutic potential against inflammatory disorders.…”

“…Also, as zerumbone is known to prevent COX-2 expression in articular tissues, it has been suggested that the compound may indirectly suppress inflammatory cytokines production and hence provide another plausible mechanism of its beneficial effects in osteoarthritis models. Besides its useful effects in osteoarthritis models, zerumbone was also found suppress osteolytic bone metastases in a dose-dependent manner in human breast cancer-bearing athymic nude mice, pointing to its potential as a therapeutic agent for osteoporosis and cancer-induced bone loss [63].…”

Phychemistry, Phytochemical, Pharmacological and Molecular Study of Zingiber Officinale Roscoe: A Review

“…Remarkably, 10-gingerol was about 50-fold more potent (IC50 = 12 versus 670 µM, respectively) than 6-gingerol [39]. Ginger and its bioactive molecules are effective in regulatory the degree of colorectal, gastric, ovarian, liver, skin, breast, and prostate cancers [40,[42][43][44][45][46][47]. Kim et al [45] have carried out an experiment in mouse models and administered Zerumbone orally and observed inhibition in a multiplicity of colonic adenocarcinomas through suppression of colonic inflammation in a dose-dependent manner.…”

Breast tumors induced by N-methyl-N-nitrosourea are damaging to bone strength, structure, and mineralization in the absence of metastasis in rats

“…(1,(6)(7)(8)24) Within the positive-feedback loop of metastatic bone disease, initiation of osteoclast activity by interleukin 8 (IL-8), (1,25) parathyroid hormone-related peptide (PTHrP), (4,26,27) and receptor activator of NF-kB ligand (RANKL) (1,28) is implicated. In turn, osteoclast activity releases growth factors in bone that promote tumor proliferation and growth, including transforming growth factor b, (29,30) bone morphogenic proteins, (31,32) and others.…”