The bone is the most common metastatic site of
breast cancer. Bone
metastasis causes
pain,
pathologic fractures, and severely reduces the quality of life.
Breast cancer causes osteolytic bone
metastasis, which is dependent on osteoclast-mediated
bone resorption. While current treatments rely on palliative anti-resorptive agents, there is a need to develop a
drug based on potential
alternative therapies. This study is the first to determine that
wedelolactone (WDL), a natural
coumarin isolated from plants, can inhibit
breast cancer-mediated osteoclastogenesis. Osteoclasts were generated from human CD14(+) monocytes cultured with
M-CSF/RANKL and WDL suppressed human osteoclast differentiation and activity in vitro in a dose-dependent manner. Moreover, WDL inhibited the upregulation of osteoclasts stimulated by MDA‑MB‑231
breast cancer cells. The activity of WDL on osteoclasts and
breast cancer-mediated osteoclastogenesis was associated with the inhibition of Akt/mammalian target of the
rapamycin signaling pathway (mTOR). Blocking Akt and mTOR by specific inhibitors significantly decreased osteoclast differentiation and
bone resorption. Furthermore, WDL regulated
breast cancer-enhanced interaction of osteoblasts and osteoclasts by decreasing
M-CSF expression in MDA‑MB‑231-stimulated osteoblasts. Thus, this study suggests that WDL may be a potential natural agent for preventing and treating bone destruction in patients with bone
metastasis due to
breast cancer.