Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Phytother Res. 2023 Jun;37(6):2262-2279. doi: 10.1002/ptr.7732. Epub 2023 Feb 1.
Distal metastases from breast cancer, especially bone metastases, are extremely common in the late stages of the disease and are associated with a poor prognosis. EMT is a biomarker of the early process of bone metastasis, and MMP-9 and MMP-13 are important osteoclastic activators. Previously, we found that meso-Hannokinol (HA) could significantly inhibit EMT and MMP-9 and MMP-13 expressions in breast cancer cells. On this basis, we further explored the role of HA in breast cancer bone metastasis. In vivo, we established a breast cancer bone metastasis model by intracardially injecting breast cancer cells. Intraperitoneal injections of HA significantly reduced breast cancer cell metastasis to the leg bone in mice and osteolytic lesions caused by breast cancer. In vitro, HA inhibited the migration and invasion of breast cancer cells and suppressed the expressions of EMT, MMP-9, MMP-13, and other osteoclastic activators. HA inhibited EMT and MMP-9 by activating the ROS/JNK pathway as demonstrated by siJNK and SP600125 inhibition of JNK phosphorylation and NAC scavenging of ROS accumulation. Moreover, HA promoted bone formation and inhibited bone resorption in vitro. In conclusion, our findings suggest that HA may be an excellent candidate for treating breast cancer bone metastasis.
乳腺癌的远处转移，特别是骨转移，在疾病晚期极为常见，且与预后不良有关。上皮间质转化（EMT）是骨转移早期过程的一个生物标志物，而 MMP-9 和 MMP-13 是重要的破骨细胞激活剂。之前，我们发现介孔汉可宁（HA）可显著抑制乳腺癌细胞中的 EMT 和 MMP-9 及 MMP-13 的表达。在此基础上，我们进一步探究了 HA 在乳腺癌骨转移中的作用。在体内，我们通过心内注射乳腺癌细胞建立了乳腺癌骨转移模型。腹腔内注射 HA 可显著减少乳腺癌细胞向小鼠腿骨的转移以及乳腺癌引起的溶骨性病变。在体外，HA 抑制了乳腺癌细胞的迁移和侵袭，并下调了 EMT、MMP-9、MMP-13 等破骨细胞激活剂的表达。通过 siJNK 和 SP600125 抑制 JNK 磷酸化以及 NAC 清除 ROS 积累，我们发现 HA 通过激活 ROS/JNK 通路抑制 EMT 和 MMP-9。此外，HA 还可促进体外的骨形成并抑制骨吸收。综上，我们的研究结果表明，HA 可能是治疗乳腺癌骨转移的一个优秀候选药物。
