Food & Chemical Toxicology, 2014, 67(5):212-221.

Additivity, antagonism, and synergy in arsenic trioxide-induced growth inhibition of C6 glioma cells: Effects of genistein, quercetin and buthionine-sulfoximine

Ellen Klauser, Michael Gülden, Edmund Maser, et al

Institute for Toxicology and Pharmacology for Natural Scientists, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, D-24105 Kiel, Germany

Arsenic trioxide (ATO) induces clinical remission in acute promyelocytic leukemia and growth inhibition in various cancer cell lines in vitro. Recently, genistein and quercetin were reported to potentiate ATO-provoked apoptosis in leukemia and hepatocellular carcinoma cells. Genistein acted via enhanced ROS generation and quercetin via glutathione depletion. Searching for potential strategies for the treatment of malignant gliomas in this study the capacity of these flavonoids to sensitize rat C6 astroglioma cells for the cytotoxic action of ATO was investigated. ATO inhibited cell growth in a concentration- and time-dependent manner. This effect was accompanied neither by enhanced radical generation nor lipid peroxidation and was not attributed to apoptosis. ATO treatment concentration-dependently increased glutathione levels. Genistein enhanced radical generation. Combined with ATO it inhibited cell growth additively. Additivity was also obtained after cotreatment with ATO and H2O2. Quercetin acted antagonistically on ATO-induced growth inhibition. Quercetin increased glutathione levels. In contrast, buthionine-sulfoximine (BSO) depleted cellular glutathione and acted synergistically with ATO. In conclusion, in C6 cells neither genistein nor quercetin are suited as sensitizing agent, in contrast to BSO. Depletion of cellular glutathione content rather than an increase of ROS generation plays a central role in the enhancement of ATO-toxicity in C6 cells.

英国《食品与化学毒理学》，2014年5月

由三氧化二砷诱导生长抑制的C6胶质瘤细胞的可加性、 拮抗作用和协同作用：金雀异黄素、 槲皮素和丁磺酸盐的影响

埃伦 卡尔劳塞，迈克尔 居尔登，埃德蒙 麦瑟，等

德国石荷州基尔大学医院毒理学和药理学研究中心

在体外三氧化二砷 (ATO) 诱导急性早幼粒细胞白血病临床缓解并且生长抑制各种癌细胞。最近，金雀异黄素和槲皮素被报道在白血病和肝细胞癌中可以增强ATO 引起的细胞凋亡。金雀异黄素通过增强 ROS 的产生和槲皮素通过消耗谷胱甘肽发挥作用。在此研究中，为了寻找潜在的恶性胶质瘤治疗方法，探究了这些黄酮类化合物使大鼠 C6 星形胶质细胞瘤细胞对ATO细胞毒害作用更加敏感的能力。ATO 以浓度和时间依赖性方式抑制细胞生长。这种效应既没有伴随着自由基产生的增强也没有发生脂质的过氧化，并且不是因为细胞凋亡。ATO 治疗浓度依赖性地提高了谷胱甘肽水平。金雀异黄素增强了自由基的生成。与ATO联合可以增强地抑制细胞生长。 ATO 与 H2O2联合治疗也可以增强。槲皮素对 ATO诱导的 生长抑制起相反作用。槲皮素增加了谷胱甘肽水平。与此相反的是，丁-磺酸盐 (BSO) 消耗了细胞内谷胱甘肽并且与 ATO 协同作用。总之，在 C6 细胞中金雀异黄素和槲皮素都不适合作为增敏剂，与BSO相比。细胞内谷胱甘肽含量的消耗而不是增加 ROS 的产量对于增强ATO 在 C6 细胞中的毒性发挥中心关键的作用。