title: Wedelolactone inhibits breast cancer-induced osteoclastogenesis by decreasing Akt/mTOR signaling.
abstract: 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.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Hsieh
authors.affiliation: Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.affiliation: Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ying-Chan
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003374:Coumarins / Q000008:administration & dosage*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000096:biosynthesis*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D003374:Coumarins; D053245:RANK Ligand; C051122:wedelolactone; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases