Université Paris Descartes, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Laboratoire d'immunologie, France.
Cell Death Dis. 2011 Aug 11;2(8):e191. doi: 10.1038/cddis.2011.73.
Organotellurides are newly described redox-catalyst molecules with original pro-oxidative properties. We have investigated the in vitro and in vivo antitumoral effects of the organotelluride catalyst LAB027 in a mouse model of colon cancer and determined its profile of toxicity in vivo. LAB027 induced an overproduction of H(2)O(2) by both human HT29 and murine CT26 colon cancer cell lines in vitro. This oxidative stress was associated with a decrease in proliferation and survival rates of the two cell lines. LAB027 triggered a caspase-independent, ROS-mediated cell death by necrosis associated with mitochondrial damages and autophagy. LAB027 also synergized with the cytotoxic drug oxaliplatin to augment its cytostatic and cytotoxic effects on colon cancer cell lines but not on normal fibroblasts. The opposite effects of LAB027 on tumor and on non-transformed cells were linked to differences in the modulation of reduced glutathione metabolism between the two types of cells. In mice grafted with CT26 tumor cells, LAB027 alone decreased tumor growth compared with untreated mice, and synergized with oxaliplatin to further decrease tumor development compared with mice treated with oxaliplatin alone. LAB027 an organotelluride catalyst compound synergized with oxaliplatin to prevent both in vitro and in vivo colon cancer cell proliferation while decreasing the in vivo toxicity of oxaliplatin. No in vivo adverse effect of LAB027 was observed in this model.
有机碲化物是新描述的氧化还原催化剂分子，具有原始的促氧化特性。我们研究了有机碲化物催化剂 LAB027 在结肠癌小鼠模型中的体外和体内抗肿瘤作用，并确定了其体内毒性特征。LAB027 在体外诱导人 HT29 和鼠 CT26 结肠癌细胞系过量产生 H(2)O(2)。这种氧化应激与两种细胞系增殖和存活率的降低有关。LAB027 通过细胞坏死引起 caspase 非依赖性、ROS 介导的细胞死亡，与线粒体损伤和自噬有关。LAB027 还与细胞毒性药物奥沙利铂协同作用，增强其对结肠癌细胞系的细胞抑制和细胞毒性作用，但对正常成纤维细胞没有作用。LAB027 对肿瘤和非转化细胞的相反作用与两种细胞类型之间还原型谷胱甘肽代谢的调节差异有关。在 CT26 肿瘤细胞移植的小鼠中，与未治疗的小鼠相比，LAB027 单独使用可降低肿瘤生长，并且与奥沙利铂协同作用可进一步降低与单独使用奥沙利铂治疗的小鼠相比肿瘤的发展。LAB027 与奥沙利铂协同作用，可防止体外和体内结肠癌细胞增殖，同时降低奥沙利铂的体内毒性。在该模型中未观察到 LAB027 的体内不良反应。
