Plumbagin Inhibits Breast Tumor Bone Metastasis and Osteolysis by Modulating the Tumor-Bone Microenvironment

Z.      Li; J.      Xiao; X.      Wu; W.      Li; Z.      Yang; J.      Xie; L.      Xu; X.      Cai; Z.      Lin; W.      Guo; J.      Luo; M.      Liu

Abstract

Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction between tumor cells and the bone marrow microenvironment drives a so-called ‘vicious cycle’ that promotes tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin may serve as a novel agent in the treatment of tumor bone metastasis.

Keywords: Plumbagin, breast cancer bone metastasis, osteolysis, microenvironment, tumor-bone interaction, osteolytic metastasis, bisphosphonates, Denosumab, osteoclast function, bone resorption, tumor metastasis, osteoblasts, osteoprotegerin, bone marrow monocyte, osteoclastogenesis.