East-West Bone & Joint Research Institute, East-West Neo Medical Center, Kyung Hee University, 149 Sangil-dong, Gangdong-gu, Seoul, Republic of Korea.
Eur J Pharmacol. 2010 Dec 15;649(1-3):135-9. doi: 10.1016/j.ejphar.2010.09.048. Epub 2010 Sep 22.
Pyrrolidine dithiocarbamate (PDTC) can form a complex with metal ions and then act as a proteasome inhibitor, which leads to tumor cell apoptosis, and could therefore be developed as an anticancer agent. In our efforts to find factors that induce PDTC-mediated apoptosis of tumor cells, the effect of serum concentration on the apoptotic activity of PDTC was investigated. PDTC could not induce MCF-7 breast tumor cell death in serum-free media but significantly induced cell death in a dose-dependent manner at concentrations of ≥25 μM in media containing 10% fetal bovine serum. PDTC-mediated cell death was also dependent on serum concentration. PDTC-mediated cell death occurred through apoptosis. Similar to that in normal FBS, PDTC-mediated apoptotic cell death was also induced in media containing dialyzed FBS, indicating that PDTC-mediated apoptosis does not require metal ions or salts, but rather proteins in fetal bovine serum. In addition, differential apoptotic effects of PDTC were not observed with inhibitors of NF-κB activation such as N-acetylcysteine (NAC), Fenofibrate and carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal (MG132) or with the metal-binding agent, 5-chloro-7-iodo-8-hydroxyquinoline (Clioquinol). These results indicate that serum is required for PDTC-mediated apoptosis and that zinc-binding compounds such as PDTC, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and Clioquinol may each have their own mechanisms by which they induce tumor cell death, even though they are all classified as zinc-binding compounds.
吡咯烷二硫代氨基甲酸盐（PDTC）可以与金属离子形成复合物，然后作为蛋白酶体抑制剂发挥作用，导致肿瘤细胞凋亡，因此可以开发为抗癌药物。在寻找诱导 PDTC 介导的肿瘤细胞凋亡的因素的过程中，我们研究了血清浓度对 PDTC 诱导凋亡活性的影响。PDTC 不能在无血清培养基中诱导 MCF-7 乳腺癌肿瘤细胞死亡，但在含 10%胎牛血清的培养基中以 25μM 以上的浓度显著诱导细胞死亡，呈剂量依赖性。PDTC 介导的细胞死亡也依赖于血清浓度。PDTC 介导的细胞死亡通过凋亡发生。与正常 FBS 中的情况类似，在含透析 FBS 的培养基中也诱导了 PDTC 介导的凋亡细胞死亡，表明 PDTC 介导的凋亡不需要金属离子或盐，而是需要胎牛血清中的蛋白质。此外，PDTC 的差异凋亡作用并未在 NF-κB 激活抑制剂如 N-乙酰半胱氨酸（NAC）、非诺贝特和苯甲酰基-L-亮氨酰-L-亮氨酰-L-亮氨酸（MG132）或金属结合剂 5-氯-7-碘-8-羟基喹啉（Clioquinol）存在时观察到。这些结果表明，PDTC 介导的凋亡需要血清，并且像 PDTC、N,N,N',N'-四（2-吡啶甲基）乙二胺（TPEN）和 Clioquinol 这样的锌结合化合物可能具有各自诱导肿瘤细胞死亡的机制，尽管它们都被归类为锌结合化合物。
