Jie Zhiwei, Wang Shiyu, Ma Qingliang, Shen Yang, Zhao Xiangde, Yu Hejun, Xie Ziang, Jiang Chao
Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
J Bone Oncol. 2022 Jun 11;35:100439. doi: 10.1016/j.jbo.2022.100439. eCollection 2022 Aug.
Breast cancer metastases to the bone can lead to a series of bone-related events that seriously affect the quality of life. Pexmetinib, a novel p38 mitogen-activated protein kinase (p38) inhibitor that has been evaluated in phase I clinical trials for myelodysplastic syndrome, but the effects of Pexmetinib on breast cancer induced osteolysis haven't been explored. Here, we found that Pexmetinib inhibited receptor activator of nuclear factor-κB ligand-induced osteoclast formation and bone resorption . Pexmetinib suppressed p38-mediated signal transducer and activator of transcription 3 (STAT3), which direct regulated transcription of the nuclear factor of activated T cells 1 (NFATc1), leading to reduced osteoclast formation. Moreover, Pexmetinib exerted anti-tumor effects in breast cancer cells via suppressing p38-mediated STAT3 activation and matrix metalloproteinases (MMPs) expression. Furthermore, Pexmetinib suppressed breast cancer-associated osteolysis . These results suggest that Pexmetinib may be a promising drug for the treatment of breast cancer-induced osteolysis.
乳腺癌转移至骨骼可导致一系列与骨相关的事件，严重影响生活质量。培美替尼是一种新型的p38丝裂原活化蛋白激酶（p38）抑制剂，已在骨髓增生异常综合征的I期临床试验中进行了评估，但培美替尼对乳腺癌诱导的骨溶解的影响尚未得到探索。在此，我们发现培美替尼可抑制核因子κB受体活化因子配体诱导的破骨细胞形成和骨吸收。培美替尼抑制p38介导的信号转导和转录激活因子3（STAT3），而STAT3直接调控活化T细胞核因子1（NFATc1）的转录，从而导致破骨细胞形成减少。此外，培美替尼通过抑制p38介导的STAT3活化和基质金属蛋白酶（MMPs）表达，对乳腺癌细胞发挥抗肿瘤作用。此外，培美替尼可抑制乳腺癌相关的骨溶解。这些结果表明，培美替尼可能是一种治疗乳腺癌诱导的骨溶解的有前景的药物。
