Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts.

Abstract

Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-β-stimulated cell viability, migration, and invasion and decreased TGF-β-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.

• Authors: Ah Young Jun, Hyun-Jeong Kim, Kwang-Kyun Park, Kun Ho Son, Dong Hwa Lee, Mi-Hee Woo, Won-Yoon Chung
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 1 Pg. 1-13 (Feb 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 23673814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzodioxoles
• Furans
• Lignans
• Osteoprotegerin
• Parathyroid Hormone-Related Protein
• RANK Ligand
• RNA, Messenger
• magnolin
• Lignin
• fargesin

Topics

• Animals
• Benzodioxoles (chemistry, pharmacology, therapeutic use)
• Bone Resorption (drug therapy, etiology)
• Breast Neoplasms (complications, drug therapy, pathology)
• Cell Line, Tumor
• Female
• Furans (chemistry, pharmacology, therapeutic use)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lignans (chemistry, pharmacology, therapeutic use)
• Lignin (chemistry, pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• Osteoblasts (drug effects, metabolism, pathology)
• Osteoclasts (drug effects, metabolism, pathology)
• Osteoprotegerin (genetics, metabolism)
• Parathyroid Hormone-Related Protein (biosynthesis)
• RANK Ligand (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)