Cheng Kai-Chun, Hung Chun-Tzu, Chen Kuo-Jen, Wu Wen-Chuan, Suen Jau-Ling, Chang Cheng-Hsien, Lu Chi-Yu, Tseng Chih-Hua, Chen Yeh-Long, Chiu Chien-Chih
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Ophthalmology, Kaohsiung Municipal Hsiao-kang Hospital, Kaohsiung, Taiwan.
Arch Immunol Ther Exp (Warsz). 2016 Apr;64(2):139-47. doi: 10.1007/s00005-015-0368-4. Epub 2015 Nov 12.
Retinoblastoma (Rb) is the most common primary intraocular malignant tumor of childhood. It is important to develop the strategy for Rb treatment. We have tested a quinolone derivative 2,9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1,2-c]quinolin-11-one (BPIQ) for its anti-cancer effects against Rb via cultured human Rb cell line Y79. Our results showed that BPIQ significantly inhibits cell growth of Y79. Furthermore, the flow cytometer-based assays and Western blotting showed that BPIQ induces the apoptosis of Y79 via increasing the level of reactive oxygen species (ROS). Besides, the activation of γH2AX, a DNA damage sensor in human Y79 cells was also observed, indicating the potential of BPIQ for causing DNA damage of Rb cells. On the contrary, BPIQ-induced apoptosis of Y79 cells was attenuated significantly by N-acetyl-L-cysteine (NAC), an ROS scavenger. The results of Western blot showed that BPIQ down-regulates the levels of anti-apoptotic proteins Bcl-2, survivin and XIAP while up-regulates the pro-apoptotic proteins Bad, Bax and Bid. Our present study demonstrated the anti-proliferative effect of BPIQ in human Y79 cells. The inhibitory effect of BPIQ on the proliferation of Y79 cells is, at least, partly mediated by the regulation of ROS and DNA damage pathway. In conclusion, BPIQ may provide an alternative option in the chemotherapeutics or chemoprevention on the Rb therapy in the future.
视网膜母细胞瘤（Rb）是儿童期最常见的原发性眼内恶性肿瘤。制定Rb的治疗策略很重要。我们通过培养的人Rb细胞系Y79测试了喹诺酮衍生物2,9-双[2-（吡咯烷-1-基）乙氧基]-6-{4-[2-（吡咯烷-1-基）乙氧基]苯基}-11H-茚并[1,2-c]喹啉-11-酮（BPIQ）对Rb的抗癌作用。我们的结果表明，BPIQ显著抑制Y79细胞的生长。此外，基于流式细胞仪的检测和蛋白质印迹法表明，BPIQ通过增加活性氧（ROS）水平诱导Y79细胞凋亡。此外，还观察到人类Y79细胞中的DNA损伤传感器γH2AX的激活，这表明BPIQ有导致Rb细胞DNA损伤的潜力。相反，ROS清除剂N-乙酰-L-半胱氨酸（NAC）显著减弱了BPIQ诱导的Y79细胞凋亡。蛋白质印迹结果表明，BPIQ下调抗凋亡蛋白Bcl-2、生存素和XIAP的水平，同时上调促凋亡蛋白Bad、Bax和Bid的水平。我们目前的研究证明了BPIQ在人Y79细胞中的抗增殖作用。BPIQ对Y79细胞增殖的抑制作用至少部分是由ROS和DNA损伤途径的调节介导的。总之，BPIQ可能为未来Rb治疗的化疗或化学预防提供一种替代选择。
