Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Neurosurgery, Shenzhen People's Hospital, Shenzhen, China.
Cell Biol Toxicol. 2019 Dec;35(6):521-539. doi: 10.1007/s10565-019-09462-y. Epub 2019 Feb 9.
Bufalin is the primary component of the traditional Chinese medicine "Chan Su," which has been widely used for cancer treatment at oncology clinics in certain countries. Evidence suggests that this compound possesses potent antitumor activities, although the exact molecular mechanism(s) require further elucidation. Therefore, this study aimed to further clarify the in vitro and in vivo antiglioma effects of bufalin and the molecular mechanism underlying the regulation of drug sensitivity. The anticancer effects of bufalin were determined by colony formation assays, apoptosis assays, and cellular redox state tests of glioma cells. Confocal microscopy was performed to determine the expression changes of the DNA damage biomarker γ-H2AX and the nuclear translocation of p53 in glioma cells. Western blotting and RT-PCR were used to detect the protein and gene expression levels, respectively. Here, we report that bufalin induced glioblastoma cell apoptosis and oxidative stress and triggered DNA damage. The critical roles of the sodium pump α1 subunit (ATP1A1) in mediating the XPO1-targeted anticancer effect of bufalin in human glioma were further confirmed. Mechanistic studies confirmed the important roles of Src and p53 signaling in mediating bufalin-induced apoptosis. Importantly, bufalin also inhibited the growth of glioma xenografts. In conclusion, our study indicated that therapies targeting the ATP1A1 and p53 signaling-mediated mitochondrial apoptotic pathways regulated by bufalin might be potential treatments for human glioma, and these findings will provide molecular bases for developing bufalin into a drug candidate for the treatment of malignant glioma.
蟾酥是中药“蟾酥”的主要成分，在某些国家的肿瘤诊所中被广泛用于癌症治疗。有证据表明，这种化合物具有很强的抗肿瘤活性，尽管确切的分子机制尚需进一步阐明。因此，本研究旨在进一步阐明蟾毒灵在体外和体内的抗神经胶质瘤作用及其调节药物敏感性的分子机制。通过集落形成实验、细胞凋亡实验和细胞氧化还原状态实验来确定蟾毒灵的抗癌作用。共聚焦显微镜用于检测神经胶质瘤细胞中 DNA 损伤生物标志物 γ-H2AX 的表达变化和 p53 的核转位。Western blot 和 RT-PCR 分别用于检测蛋白和基因表达水平。在这里，我们报告蟾毒灵诱导神经胶质瘤细胞凋亡和氧化应激，并引发 DNA 损伤。进一步证实了钠泵 α1 亚基（ATP1A1）在介导蟾毒灵靶向 XPO1 的抗癌作用中的关键作用。机制研究证实了Src 和 p53 信号在介导蟾毒灵诱导的细胞凋亡中的重要作用。重要的是，蟾毒灵还抑制了神经胶质瘤异种移植的生长。总之，我们的研究表明，针对由蟾毒灵调节的 ATP1A1 和 p53 信号介导的线粒体凋亡途径的治疗方法可能是治疗人类神经胶质瘤的潜在方法，这些发现将为将蟾毒灵开发为治疗恶性神经胶质瘤的药物提供分子基础。
