Isothiocyanate NB7M causes selective cytotoxicity, pro-apoptotic signalling and cell-cycle regression in ovarian cancer cells
Isothiocyanate NB7M causes selective cytotoxicity, pro-apoptotic signalling and cell-cycle regression in ovarian cancer cells
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DOI：
10.1038/sj.bjc.6604778
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发表时间：
2008-11-25
影响因子：
8.8
通讯作者：
Brard, L.
中科院分区：
文献类型：
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作者：
Singh, R. K.;Lange, T. S.;Brard, L.
本报告确认吲哚-3-乙基异硫氰酸酯NB7M是一种有效的细胞毒剂，对来自各种肿瘤类型的细胞株具有选择性活性。与对照细胞(TCL-1和HTR-8；IC50与15mM相似)相比，卵巢癌细胞株对NB7M表现出敏感性(2.5mM时细胞毒作用为60-70%)。在由美国国家癌症研究所(NCI)(NCI60癌细胞分析)进行的筛查中，NB7M(NSC746077)的生长抑制率高达100%，IC50在0.1至10µM之间，具体取决于所研究的细胞系。以SKOV-3卵巢癌细胞为模型，对其细胞毒作用机制进行了分析。NB7M导致PARP-1失活、染色质凝集、DNA缺口、caspase-9、-8、-3激活、线粒体跨膜去极化能力丧失和促凋亡丝裂原激活蛋白激酶(p38、SAP/JNK)上调。NB7M下调促存活蛋白(PI-3K、AKT、IKKα)、转录因子NF-kappaB的磷酸化，下调DNA-PK和Ax1受体酪氨酸激酶的表达。亚细胞毒性剂量NB7M抑制DNA合成，引起Gi期细胞周期停滞，上调p27表达。本报告提示NB7M是一种体外选择性细胞毒剂，可用于卵巢肿瘤和某些其他肿瘤细胞株的体外杀伤。此外，NB7M作为一种生长/细胞周期抑制药，可能被开发为治疗卵巢癌的潜在治疗药物。
The present report identifies indole-3-ethyl isothiocyanate NB7M as a potent cytotoxic agent with selective activity against cell lines derived from various tumour types. Ovarian cancer cell lines showed sensitivity to NB7M (60-70% cytotoxicity at 2.5 mu M), in contrast to control cells (TCL-1 and HTR-8; IC50 similar to 15 mu M). In a screen performed by the National Cancer Institute (NCI) (NCI60 cancer cell-line assay) NB7M (NSC746077) reduced growth up to 100% with an IC50 between 0.1 and 10 mu M depending on the cell line studied. Using SKOV-3 ovarian cancer cells as a model, mechanisms of cytotoxicity were analysed. NB7M caused hallmarks of apoptosis such as PARP-1 deactivation, chromatin condensation, DNA nicks, activation of caspases-9, -8, -3, loss of mitochondrial transmembrane depolarisation potential and upregulation of pro-apoptotic mitogen activated protein kinases (p38, SAP/JNK). NB7M downregulated phosphorylation of prosurvival kinases (PI-3K, AKT, IKK alpha), transcription factor NF-kappa B, and expression of DNA-Pk and AXL receptor tyrosine kinase. Subcytotoxic doses of NB7M inhibited DNA synthesis, caused GI-phase cell-cycle arrest and upregulated p27 expression. The present report suggests that NB7M is a selective cytotoxic agent in vitro for cell lines derived from ovarian and certain other tumours. In addition, NB7M acts as a growth/cell-cycle-suppressing agent and may be developed as a potential therapeutic drug to treat ovarian cancer.