Lee Joo Hyun, Lee Han-Beom, Jung Gum O, Oh Jung Taek, Park Dong Eun, Chae Kwon Mook
Division of Hepatobiliary Surgery, Department of Surgery, Wonkwang University School of Medicine & Hospital, Iksan, Korea.
J Korean Surg Soc. 2013 Dec;85(6):249-60. doi: 10.4174/jkss.2013.85.6.249. Epub 2013 Nov 26.
To investigate the chemotherapeutic effect of quercetin against cancer cells, signaling pathway of apoptosis was explored in human pancreatic cells.
Various anticancer drugs including adriamycin, cisplatin, 5-fluorouracil (5-FU) and gemcitabine were used. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-nyltetra zolium bromide assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole nuclei staining and flow cytometry in PANC-1 cells treated with 50 µg/mL quercetin for 24 hours. Expression of endoplas mic reticulum (ER) stress mediators including, Grp78/Bip, p-PERK, PERK, ATF4, ATF6 and GADD153/CHOP proteins were measured by Western blot analysis. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123. Quercetin induced the apoptosis of PANC-1, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G0/G1 fraction of cell cycle increase. But not adriamycin, cisplatin, gemcitabine, and 5-FU. PANC-1 cells were markedly sensitive to quercetin.
Treatment with quercetin resulted in the increased accumulation of intracellular Ca(2+) ion. Treatment with quercetin also increased the expression of Grp78/Bip and GADD153/CHOP protein and induced mitochondrial dysfunction. Quercetin exerted cytotoxicity against human pancreatic cancer cells via ER stress-mediated apoptotic signaling including reactive oxygen species production and mitochondrial dysfunction.
These data suggest that quercetin may be an important modulator of chemosensitivity of cancer cells against anticancer chemotherapeutic agents.
研究槲皮素对癌细胞的化疗作用，探讨其在人胰腺细胞中的凋亡信号通路。
使用了包括阿霉素、顺铂、5-氟尿嘧啶（5-FU）和吉西他滨在内的多种抗癌药物。通过3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐法测定细胞活力。在用50μg/mL槲皮素处理24小时的PANC-1细胞中，通过4′-6-二脒基-2-苯基吲哚细胞核染色和流式细胞术测定凋亡情况。通过蛋白质印迹分析测定内质网（ER）应激介质包括Grp78/Bip、p-PERK、PERK、ATF4、ATF6和GADD153/CHOP蛋白的表达。用JC-1、罗丹明123进行荧光染色测定线粒体膜电位。槲皮素诱导PANC-1细胞凋亡，其特征为核酸和基因组DNA片段化、染色质浓缩以及细胞周期亚G0/G1期分数增加。但阿霉素、顺铂、吉西他滨和5-FU无此作用。PANC-1细胞对槲皮素明显敏感。
槲皮素处理导致细胞内Ca(2+)离子积累增加。槲皮素处理还增加了Grp78/Bip和GADD153/CHOP蛋白的表达并诱导线粒体功能障碍。槲皮素通过内质网应激介导的凋亡信号，包括活性氧产生和线粒体功能障碍，对人胰腺癌细胞发挥细胞毒性作用。
这些数据表明槲皮素可能是癌细胞对抗癌化疗药物化疗敏感性的重要调节剂。
