Induction of Apoptosis and Cell Cycle Arrest by Imexon in Human Pancreatic Cancer Cell Lines
Induction of Apoptosis and Cell Cycle Arrest by Imexon in Human Pancreatic Cancer Cell Lines
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DOI：
10.1385/ijgc:36:1:015
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发表时间：
2005-08-01
影响因子：
1.6
通讯作者：
Fukushima, Shoji
中科院分区：
文献类型：
--
作者：
Dorr, Robert T.;Raymond, Mary Ann;Fukushima, Shoji
Imexon 是一种含氮丙啶的小分子，目前处于 I 期临床试验中。该药物已被证明可以与硫醇结合并增加细胞内氧化剂，从而诱导血液癌细胞凋亡。众所周知，胰腺癌对氧化敏感，这表明这种疾病可能是该药物的合适靶点。目前的报告检查了伊美克在胰腺细胞中的活性。 Imexon 在六种人胰腺癌细胞 (PCC) 系中诱导浓度依赖性和时间依赖性细胞凋亡。 SRB 测定的生长抑制的平均 IC50 (SD) 为 200 (101) mu M，暴露 48 小时，范围为 64-358 mu M。细胞杀伤是时间表依赖性的，有利于暴露时间 >= 48 小时。 Imexon 处理的 MiaPaCa-2 细胞在暴露于浓度 = 48 小时后经历非致死性生长停滞，MiaPaCa-2 细胞停滞在 G(2) 期，并检测到激活的半胱天冬酶 3、8 和 9。暴露于 IC80 浓度的伊美克 72 小时后，通过 CMXRos 染色检测到细胞表现出线粒体膜电位的损失。然而，除非使用≥400μM的极高浓度，否则还原的细胞硫醇不会损失。相比之下，活性氧（ROS）以剂量依赖性方式升高，从非常低的伊美克浓度开始。 Imexon 还以 100 mg/kg/d 剂量持续 9 天显着抑制 SCID 小鼠中 MiaPaCa-2 肿瘤的生长。肿瘤生长抑制 (% T/C) 为对照的 27%，肿瘤生长延迟为 21 天，根据 NCI 标准，这表明是一种活性药物。根据正在进行的 I 期试验的初步结果，可达到对人类 PCC 具有细胞毒性的伊美克水平。 Imexon 在体外似乎对 PCC 具有活性，并且具有全新的作用机制，涉及 G(2) 阻滞、ROS 积累和诱导细胞凋亡。
Imexon is an aziridine-containing small molecule currently in Phase I clinical trials. This agent has been shown to bind to thiols and increase intracellular oxidants, inducing apoptosis in hematologic cancer cells. Pancreatic cancers are known to be sensitive to oxidation, suggesting this disease may be an appropriate target for this agent. The current report examines the activity of imexon in pancreatic cells. Imexon induced concentration-dependent and time-dependent apoptosis in a panel of six human pancreatic carcinoma cell (PCC) lines. The mean IC50 (SD) for growth inhibition by the SRB assay was 200 (101) mu M for a 48 h exposure with a range of 64-358 mu M. Cell killing was schedule-dependent, favoring exposure times >= 48 h. Imexon-treated MiaPaCa-2 cells underwent non-lethal growth arrest following exposure to concentrations = 48 h, the MiaPaCa-2 cells arrested in G(2) phase and activated caspases 3, 8, and 9 were detected. After a 72 h exposure to the IC80 concentration of imexon, cells exhibited a loss of mitochondrial membrane potential detected by CMXRos staining. However, there was no loss of reduced cellular thiols unless very high concentrations of >= 400 mu M were used. In contrast, reactive oxygen species (ROS) were elevated in a dose-dependent fashion, starting at very low imexon concentrations. Imexon also significantly inhibited MiaPaCa-2 tumor growth in SCID mice at 100 mg/kg/d for 9 d. The tumor growth inhibition (% T/C) was 27% of control, and the tumor growth delay was 21 d, indicating an active agent by NCI standards.The levels of imexon that are cytotoxic in human PCC's are achievable based on the preliminary results of the ongoing Phase I trial. Imexon appears to be active against PCCs in vitro and has an entirely novel mechanism of action involving G(2) arrest, accumulation of ROS, and the induction of apoptosis.