Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
J Neurooncol. 2011 Jan;101(1):41-8. doi: 10.1007/s11060-010-0237-2. Epub 2010 Jun 12.
Various antidepressants, mainly tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have exhibited potent anticancer properties in different cancer cell types. In the present study, desipramine (DMI), a representative of TCAs, was examined with respect to its apoptosis-inducing activity in rat C6 glioma cells and the underlying mechanism of action. DMI induced typical apoptotic morphology of chromatin condensation in rat glioma C6 cells and activated intracellular caspase 9 and caspase 3 with no change in mitochondrial membrane potential. Simultaneously, DMI significantly elevated expression of endoplasmic reticulum stress regulator CHOP/GADD153 and its targeting molecule GADD34. However, knockdown of CHOP by CHOP-specific short interfering RNA (siRNA) could decrease the activity of intracellular caspase 3 and the cytotoxicity of DMI to C6 cells. These results revealed that the CHOP-dependent endoplasmic reticulum (ER) stress pathway is responsible for DMI-induced apoptosis in C6 cells.
各种抗抑郁药，主要是三环类抗抑郁药（TCAs）和选择性 5-羟色胺再摄取抑制剂（SSRIs），在不同的癌细胞类型中表现出强大的抗癌特性。在本研究中，以去甲丙咪嗪（DMI）为例，研究了其在大鼠 C6 神经胶质瘤细胞中诱导细胞凋亡的活性及其作用机制。DMI 诱导大鼠神经胶质瘤 C6 细胞出现典型的染色质凝聚的凋亡形态，并激活细胞内 caspase-9 和 caspase-3，而线粒体膜电位没有变化。同时，DMI 显著上调内质网应激调节剂 CHOP/GADD153 及其靶向分子 GADD34 的表达。然而，CHOP 特异性短发夹 RNA（siRNA）敲低 CHOP 可降低细胞内 caspase-3 的活性和 DMI 对 C6 细胞的细胞毒性。这些结果表明，CHOP 依赖性内质网（ER）应激途径负责 DMI 诱导 C6 细胞凋亡。
