State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.
Eur J Pharm Sci. 2013 Mar 12;48(4-5):658-67. doi: 10.1016/j.ejps.2012.12.023. Epub 2013 Jan 10.
Pancreatic cancer is one of the most malignant tumor diseases with the characters of aggressive growth and metastasis. With the inefficiency of the current therapeutics, new potential targets and new therapeutic agents for healing of pancreatic cancer are critically needed. We have previously found a small molecule, named 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP, NSC number: 48160), which can freeze the intermediate of Ras-GTP hydrolysis in the open non-signaling conformation with high affinity and high specificity in silico. In this work, we studied the effect and mechanism of TBMMP on two pancreatic cancer cell lines, CFPAC-1 and BxPC-3. The results showed that TBMMP could restrain the growth of the pancreatic cancer cells with IC(50) value 84.3 μM for CPFAC-1 and 94.5 μM for BxPC-3, respectively. Additionally, TBMMP increased cytochrome c release, reduced mitochondrial membrane potential, activated caspase-3, -9, elevated ROS and increased expression of the Bax in the pancreatic cancer cell lines. The results indicated that TBMMP induced the apoptosis of pancreatic cancer cells through the mitochondrial pathway. Further, we also found that TBMMP could suppress the metastasis of both pancreatic cancer cells in vitro. Taken together, we proposed that TBMMP might be a therapeutic potential lead for treating patients with pancreatic cancer.
胰腺癌是最具恶性肿瘤特征的肿瘤疾病之一，具有侵袭性生长和转移的特征。由于目前治疗方法的效果不佳，迫切需要新的潜在靶点和新的治疗药物来治愈胰腺癌。我们之前发现了一种小分子，名为 4-叔丁基-2-[(环己基氨基)甲基]-6-甲基苯酚（TBMMP，NSC 编号：48160），它可以在计算机模拟中以高亲和力和高特异性将 Ras-GTP 水解的中间体冷冻在开放的非信号构象中。在这项工作中，我们研究了 TBMMP 对两种胰腺癌细胞系 CFPAC-1 和 BxPC-3 的作用和机制。结果表明，TBMMP 能够抑制胰腺癌细胞的生长，其对 CFPAC-1 的 IC50值为 84.3 μM，对 BxPC-3 的 IC50值为 94.5 μM。此外，TBMMP 增加了细胞色素 c 的释放，降低了线粒体膜电位，激活了 caspase-3、-9，增加了 ROS 的产生，并增加了 Bax 在胰腺癌细胞系中的表达。结果表明，TBMMP 通过线粒体途径诱导了胰腺癌细胞的凋亡。此外，我们还发现 TBMMP 可以抑制两种胰腺癌细胞在体外的转移。综上所述，我们提出 TBMMP 可能是治疗胰腺癌患者的潜在治疗先导化合物。
