7-甲基吲哚乙基异硫氰酸酯导致子宫内膜癌细胞中 ROS 介导的细胞凋亡和细胞周期停滞。
7 Methyl indole ethyl isothiocyanate causes ROS mediated apoptosis and cell cycle arrest in endometrial cancer cells.
机构信息
Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02905, USA.
出版信息
Gynecol Oncol. 2012 Aug;126(2):252-8. doi: 10.1016/j.ygyno.2012.04.041. Epub 2012 May 2.
OBJECTIVE
Chemotherapy options for advanced endometrial cancer are limited and newer therapeutic agents are urgently needed. This study describes the therapeutic potential of 7 Methyl-indole ethyl isothiocyanate (7Me-IEITC) in endometrial cancer cell lines.
METHODS
7Me-IEITC was synthesized in our laboratory. The cell viability of 7Me-IEITC treated ECC-1 and KLE endometrial cancer cell was determined by MTS assay. Morphology and apoptosis were further confirmed by DAPI-staining and TUNEL assay. The measurement of reactive oxygen species (ROS), mitochondrial transmembrane depolarization potential (ΔΨm) and cell cycle phase was determined by FACS analysis. Expression of proteins involved in apoptosis, survival and cell-cycle progression was analyzed by Western blotting.
RESULTS
7Me-IEITC reduced the viability of the ECC-1 and KLE cancer cell-lines (IC(50)~2.5-10 μM) in a dose dependent fashion. 7Me-IEITC treatment caused mitochondrial transmembrane potential reduction, elevated the production of ROS, leading to activation of apoptosis in endometrial cancer KLE and ECC-1 cells. 7Me-IEITC treatment activated Bad, suppressed Bcl2 phosphorylation followed by PARP-1 deactivation and caspase 3 and 7 activation. 7Me-IEITC treatment arrested the progression of KLE cells in S-phase and caused CDC25 and cyclin-D1 downregulation. Pre-treatment with ascorbic acid abrogated 7Me-IEITC induced apoptosis in ECC-1 and KLE cells, suggesting that 7Me-IEITC mediated cytotoxicity is primarily through ROS production.
CONCLUSION
7Me-IEITC demonstrated promising cytotoxic effects in endometrial cancer cell line model.
目的
晚期子宫内膜癌的化疗选择有限，迫切需要新的治疗药物。本研究描述了 7-甲基吲哚乙基异硫氰酸酯（7Me-IEITC）在子宫内膜癌细胞系中的治疗潜力。
方法
7Me-IEITC 由我们实验室合成。用 MTS 法测定 7Me-IEITC 处理的 ECC-1 和 KLE 子宫内膜癌细胞的细胞活力。通过 DAPI 染色和 TUNEL 检测进一步确认形态和细胞凋亡。通过 FACS 分析测定活性氧（ROS）、线粒体跨膜去极化电位（ΔΨm）和细胞周期相的测量。通过 Western blot 分析测定凋亡、存活和细胞周期进展相关蛋白的表达。
结果
7Me-IEITC 以剂量依赖的方式降低了 ECC-1 和 KLE 癌细胞系的活力（IC50~2.5-10 μM）。7Me-IEITC 处理导致线粒体跨膜电位降低，ROS 产量增加，导致子宫内膜癌 KLE 和 ECC-1 细胞凋亡激活。7Me-IEITC 处理激活 Bad，抑制 Bcl2 磷酸化，随后 PARP-1 失活和 caspase 3 和 7 激活。7Me-IEITC 处理使 KLE 细胞在 S 期停滞，并导致 CDC25 和细胞周期蛋白 D1 下调。抗坏血酸预处理消除了 7Me-IEITC 诱导的 ECC-1 和 KLE 细胞凋亡，表明 7Me-IEITC 介导的细胞毒性主要通过 ROS 产生。
结论
7Me-IEITC 在子宫内膜癌细胞系模型中显示出有希望的细胞毒性作用。
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