Ouyang Zhengxiao, Guo Xiaoning, Chen Xia, Liu Bo, Zhang Qiang, Yin Ziqing, Zhai Zanjing, Qu Xinhua, Liu Xuqiang, Peng Dan, Shen Yi, Liu Tang, Zhang Qing
Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
Department of Orthopedics, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
Oncotarget. 2017 Dec 4;9(2):1868-1884. doi: 10.18632/oncotarget.22930. eCollection 2018 Jan 5.
Bone is the most common target organ of metastasis of breast cancers. This produces considerable morbidity due to skeletal-related events, and severely reduces the quality of life. Increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of hypericin, a natural plant compound, led us to investigate whether hypericin could inhibit bone metastasis and osteolysis caused by breast cancer. We find that hypericin inhibited the upregulation of osteoclasts stimulated by breast cancer cells. The activity of hypericin on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of NFATc1 signaling pathway and attenuation of Ca oscillation. Furthermore, hypericin suppresses invasion and migration in breast cancer cells, but has little effect on breast cancer-cell induced RANKL/OPG ratio in osteoblast or the expression of osteoclast-activating factors. Administration of hypericin could reduce tumor burden, osteolysis induced by direct inoculation of MDA-MB-231 cells into the bone marrow cavity of the tibia as well as metastasis of bone and improve survival in an experimental metastasis model by intracardiac injection of MDA-MB-231 breast cancer cells. Taken together, these results suggest that hypericin may be a potential natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.
骨是乳腺癌最常见的转移靶器官。这会因骨相关事件导致相当高的发病率，并严重降低生活质量。破骨细胞活性增加与骨微环境中乳腺癌的生长有关。我们之前观察到天然植物化合物金丝桃素具有抗破骨细胞活性，这促使我们研究金丝桃素是否能够抑制乳腺癌引起的骨转移和骨溶解。我们发现金丝桃素抑制了乳腺癌细胞刺激引起的破骨细胞上调。金丝桃素对破骨细胞以及乳腺癌介导的破骨细胞生成的作用与抑制NFATc1信号通路和减弱钙振荡有关。此外，金丝桃素抑制乳腺癌细胞的侵袭和迁移，但对乳腺癌细胞诱导的成骨细胞中RANKL/OPG比值或破骨细胞激活因子的表达影响很小。给予金丝桃素可以减轻肿瘤负荷、减少将MDA-MB-231细胞直接接种到胫骨骨髓腔中诱导的骨溶解以及骨转移，并提高通过心内注射MDA-MB-231乳腺癌细胞建立的实验性转移模型中的生存率。综上所述，这些结果表明金丝桃素可能是预防和治疗乳腺癌骨转移患者骨破坏的一种潜在天然药物。
