Wedelolactone inhibits breast cancer-induced osteoclastogenesis by decreasing Akt/mTOR signaling

The bone is the most common metastatic site of breast cancer. Bone metastasis causes pain, pathologic frac- tures, and severely reduces the quality of life. Breast cancer causes osteolytic bone metastasis, which is dependent on osteo - clast-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 differenti - ation 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 poten - tial natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.