Acriflavine enhances radiosensitivity of colon cancer cells through endoplasmic reticulum stress-mediated apoptosis

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• 作者：Min-Jin Lim^a ; Ji-Yeon Ahn^a ; Youngsoo Han^b ; Chi-ho Yu^a ; Mi-Hyoung Kim^a ; Sae-lo-oom Lee^a ; Dae-Seog Lim^c ; ¹ ; ^{dslim@cha.ac.kr} ; Jie-Young Song^a ; ¹ ; ^{immu@kirams.re.kr}
• 关键词：Acriflavine ; Radiosensitivity ; p53 ; ER stress
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2012
• 期刊代码：127_13572725
• 类别：med
• 出版时间：August, 2012
• 卷：44
• 期：8
• 页码：1214-1222
• 文件大小：1323 K

摘要

Radiotherapy (RT) is one of the most effective tools in the clinical treatment of cancer. Because the tumor suppressor p53 plays a central role in radiation-mediated responses, including cell cycle-arrest and apoptosis, a number of studies have suggested that p53 could be a useful therapeutic target of anti-cancer agents. Accordingly, we sought to discover a new agent capable of increasing p53 activity. HCT116 colon cancer cells, containing wild-type p53, were stably transfected with a p53 responsive-luciferase (p53-Luc) reporter gene. A cell-based high-throughput screen of 7920 synthetic small molecules was performed in duplicate. Of the screened compounds, acriflavine (ACF) significantly increased p53-Luc activity in a concentration-dependent manner without causing toxicity. Pretreatment with ACF enhanced the induction of p53 protein expression and phosphorylation on serine 15 by 纬-irradiation. Clonogenic assays showed that ACF pretreatment also potentiated radiation-induced cell death. The combination of irradiation and ACF treatment induced mitochondrial release of cytochrome c and significant activation of caspase-3 with PARP cleavage in colon cancer cells, demonstrating typical apoptotic cell death. Combined treatment with ACF and radiation increased the expression of Bax and Bad, while decreasing expression of Bcl-2. In addition, the ACF/radiation treatment combination induced endoplasmic reticulum (ER) stress responses mediated by IRE1伪 (inositol-requiring transmembrane kinase and endonuclease 1伪), eIF-2伪 (eukaryotic initiation factor 2伪), caspase-2/12, and CHOP (C/EBP homologous protein). The knockdown of IRE1伪 by siRNA inhibited the apoptotic cell death induced by ACF/radiation treatment. In vivo studies showed that combined treatment with ACF and radiation significantly inhibited the growth of tumors in colorectal cancer xenografted mice. These results indicate that ACF acts through p53-dependent mitochondrial pathways and ER stress signals, and could be a promising radiosensitizer.