Institute of Radiation Medicine, Fudan University, Shanghai, China.
Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.
PLoS One. 2013 Dec 19;8(12):e84610. doi: 10.1371/journal.pone.0084610. eCollection 2013.
Norcantharidin (NCTD), a demethylated analog of cantharidin derived from blister beetles, has attracted considerable attentions in recent years due to their definitely toxic properties and the noteworthy advantages in stimulating bone marrow and increasing the peripheral leukocytes. Hence, it is worth studying the anti-tumor effect of NCTD on human prostate cancer cells DU145. It was found that after the treatment of NCTD with different concentrations (25-100 μM), the cell proliferation was significantly inhibited, which led to the appearance of micronucleus (MN). Moreover, the cells could be killed in a dose-/time-dependent manner along with the reduction of PCNA (proliferating cell nuclear antigen) expression, destruction of mitochondrial membrane potential (MMP), down-regulation of MnSOD, induction of ROS, depletion of ATP, and activation of AMPK (Adenosine 5'-monophosphate -activated protein kinase) . In addition, a remarkable release of cytochrome c was found in the cells exposed to 100 μM NCTD and exogenous SOD-PEG could eliminate the generation of NCTD-induced MN. In conclusion, our studies indicated that NCTD could induce the collapse of MMP and mitochondria dysfunction. Accumulation of intercellular ROS could eventually switch on the apoptotic pathway by causing DNA damage and depleting ATP.
去甲基斑蝥素（NCTD）是一种从斑蝥中提取的斑蝥素的去甲基类似物，由于其明确的毒性特性和刺激骨髓、增加外周白细胞的显著优势，近年来引起了相当多的关注。因此，研究 NCTD 对人前列腺癌细胞 DU145 的抗肿瘤作用是值得的。结果发现，用不同浓度（25-100 μM）的 NCTD 处理后，细胞增殖明显受到抑制，导致微核（MN）的出现。此外，细胞可以被剂量/时间依赖性杀死，同时伴随着 PCNA（增殖细胞核抗原）表达的减少、线粒体膜电位（MMP）的破坏、MnSOD 的下调、ROS 的诱导、ATP 的耗竭以及 AMPK（5'-单磷酸腺苷激活的蛋白激酶）的激活。此外，在暴露于 100 μM NCTD 的细胞中发现细胞色素 c 显著释放，外源性 SOD-PEG 可以消除 NCTD 诱导的 MN 的产生。总之，我们的研究表明，NCTD 可以诱导 MMP 的崩溃和线粒体功能障碍。细胞内 ROS 的积累最终可以通过引起 DNA 损伤和耗尽 ATP 来激活凋亡途径。
