Lee Jong-Ho, Kim Bongjun, Jin Won Jong, Kim Jung-Wook, Kim Hong-Hee, Ha Hyunil, Lee Zang Hee
Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
Korean Medicine-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea.
Biochem Pharmacol. 2014 Sep 1;91(1):51-60. doi: 10.1016/j.bcp.2014.06.005. Epub 2014 Jun 11.
Bone is a preferred site of metastasis from breast cancer, and increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of Trolox, a vitamin E analog, led us to investigate whether Trolox inhibits bone metastasis and osteolysis caused by breast cancer. Administration of Trolox markedly inhibited osteolytic bone metastasis in an experimental metastasis model by intracardiac injection of 4T1 breast cancer cells. Trolox inhibited proliferation of 4T1 cells in the bone marrow but not in the mammary fat pad. In addition, Trolox could reduce tumor burden, osteolysis, and prostaglandin E2 (PGE2) production induced by direct inoculation of 4T1 cells into the marrow cavity of the tibia. Trolox decreased the migratory and invasive activities of 4T1 cells via PGE2-dependent and independent mechanisms. It also inhibited the ability of 4T1 cells to stimulate the expression of receptor activator of nuclear factor-κB ligand (RANKL), a key cytokine for osteoclast differentiation factor, in osteoblasts. In addition, Trolox suppressed RANKL expression in osteoblasts induced by soluble factors from 4T1 cells. Furthermore, Trolox suppressed 4T1 cell-induced osteoclast differentiation in the co-culture of bone marrow cells and osteoblasts via both PGE2-dependent and independent mechanisms. Taken together, these results suggest that Trolox inhibits breast cancer cell-induced osteoclast differentiation and the invasive behavior of cancer cells through PGE2-dependent and independent mechanisms, thereby suppressing osteolytic bone metastasis of breast cancer.
骨是乳腺癌转移的首选部位，破骨细胞活性增加与乳腺癌在骨微环境中的生长有关。我们之前观察到维生素E类似物Trolox具有抗破骨细胞活性，这促使我们研究Trolox是否能抑制乳腺癌引起的骨转移和骨溶解。在通过心内注射4T1乳腺癌细胞建立的实验性转移模型中，给予Trolox可显著抑制溶骨性骨转移。Trolox抑制4T1细胞在骨髓中的增殖，但不抑制其在乳腺脂肪垫中的增殖。此外，Trolox可减轻直接将4T1细胞接种到胫骨骨髓腔所诱导的肿瘤负荷、骨溶解和前列腺素E2（PGE2）生成。Trolox通过PGE2依赖性和非依赖性机制降低4T1细胞的迁移和侵袭活性。它还抑制4T1细胞刺激成骨细胞中核因子κB受体激活剂配体（RANKL）表达的能力，RANKL是破骨细胞分化因子的关键细胞因子。此外，Trolox抑制4T1细胞可溶性因子诱导的成骨细胞中RANKL的表达。此外，Trolox通过PGE2依赖性和非依赖性机制在骨髓细胞和成骨细胞共培养中抑制4T1细胞诱导的破骨细胞分化。综上所述，这些结果表明，Trolox通过PGE2依赖性和非依赖性机制抑制乳腺癌细胞诱导的破骨细胞分化和癌细胞的侵袭行为，从而抑制乳腺癌的溶骨性骨转移。
