title: Obtusifolin suppresses phthalate esters-induced breast cancer bone metastasis by targeting parathyroid hormone-related protein.
abstract: This study is the first to demonstrate that parathyroid hormone-related protein (PTHrP), produced by human breast cancer cells after exposure to phthalate esters, contributes to bone metastasis by increasing osteoclastogenesis. This is also the first to reveal that obtusifolin reverses phthalate esters-mediated bone resorption. Human breast cancer cells were treated with dibutyl phthalate (DBP), harvested in conditioned medium, and cultured to osteoblasts or osteoclasts. Cultures of osteoblasts with DBP-MDA-MB-231-CM increased the osteoclastogenesis activator RANKL (receptor activator of nuclear factor κ-B ligand) and M-CSF (macrophage colony-stimulating factor). PTHrP was secreted in MDA-MB-231 cells. DBP-MDA-MB-231-CM reduced osteoblasts to produce osteoprotegerin, an osteoclastogenesis inhibitor, while DBP mediated PTHrP up-regulation, increasing IL-8 secretion in MDA-MB-231 and contributing to breast cancer-mediated osteoclast differentiation and bone resorption. Obtusifolin, a major bioactive compound present in Cassia tora L., suppressed phthalate esters-mediated bone resorption. Therefore, obtusifolin may be a novel anti-breast-cancer bone metastasis agent.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, ‡Institute of Clinical Medicine, College of Medicine, §Department of Public Health, College of Health Science, ∥School of Medicine, College of Medicine, ⊥Research Center for Environmental Medicine, Kaohsiung Medical University , Kaohsiung 807, Taiwan.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.forename: Tsu-Nai
authors.initials: TN
authors.lastname: Wang
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D001862:Bone Resorption; D002366:Cassia / Q000737:chemistry; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004952:Esters / Q000009:adverse effects*; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D010795:Phthalic Acids / Q000009:adverse effects*; D053245:RANK Ligand
chemical_list: D000880:Anthraquinones; D004365:Drugs, Chinese Herbal; D004952:Esters; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D010795:Phthalic Acids; D053245:RANK Ligand; C546709:obtusifolin; C032279:phthalic acid; D016173:Macrophage Colony-Stimulating Factor
keywords: Cassia tora; PTHrP; obtusifolin; osteoclastogenesis; phthalate