二硫苏糖醇通过激活转录因子 3 增强顺铂的细胞毒性。
Enhancement of cisplatin cytotoxicity by disulfiram involves activating transcription factor 3.
机构信息
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Box 926, Ottawa, ON, K1H 8L6, Canada.
出版信息
Anticancer Res. 2012 Jul;32(7):2679-88.
BACKGROUND
Activating transcription factor 3 (ATF3), a stress-inducible gene, is a regulator of cisplatin-induced cytotoxicity, and enhancement of the ATF3 expression potentiates this cytotoxicity.
MATERIALS AND METHODS
ATF3 expression and its binding to the transcription target CHOP were evaluated by western blot and chromatin immunoprecipitation (ChIP), respectively, in a panel of five cell lines (WI38, MCF7, PC3, A549). MTT assays were employed to assess the effects of many drugs, including disulfiram, on cell viability.
RESULTS
ATF3 protein expression was up-regulated after cytotoxic doses of cisplatin treatment and it directly bound to the CHOP gene promoter, increasing this pro-apoptotic protein's expression. In a library screen of 1200 compounds, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was synergistic and likely due to their ability to induce ATF3 independently.
CONCLUSION
Understanding the role of ATF3 in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug's efficacy.
背景
激活转录因子 3（ATF3）是一种应激诱导基因，是顺铂诱导细胞毒性的调节剂，增强 ATF3 的表达可增强这种细胞毒性。
材料和方法
通过 Western blot 和染色质免疫沉淀（ChIP）分别评估了五个细胞系（WI38、MCF7、PC3、A549）中 ATF3 表达及其与转录靶标 CHOP 的结合。MTT 测定用于评估包括敌百虫在内的多种药物对细胞活力的影响。
结果
顺铂细胞毒性剂量处理后，ATF3 蛋白表达上调，直接与 CHOP 基因启动子结合，增加了这种促凋亡蛋白的表达。在对 1200 种化合物的文库筛选中，二硫代氨基甲酸盐药物敌百虫被鉴定为顺铂细胞毒性的增强剂。这种增强的细胞毒性作用是协同的，可能是由于它们能够独立诱导 ATF3。
结论
了解 ATF3 在顺铂诱导细胞毒性中的作用将导致新的治疗方法，从而提高这种药物的疗效。
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