Abstract
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 H2O2 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.
Highlights
Growth factors trigger the production of hydrogen peroxide (H2O2) that leads to mitogenactivated protein kinase activation and DNA synthesis, a phenomenon inhibited by antioxidant molecules.[5,6]
This study provides pre-clinical evidence that the organotelluride catalyst LAB027, a prototypical member of family of the ‘sensor/effector’ multifunctional redox catalyst agents, is a new candidate molecule to treat colon cancer either alone or in combination with oxaliplatin
The most likely explanation for this amplifying effect is an association of oxygen radical and H2O2 formation at the quinone and oxidation of cellular thiols catalyzed by tellurium in the presence of H2O2
Summary
Incubation of CT26 and HT29 cells with increasing amounts of LAB027 did not significantly alter SOD, catalase and glutathione reductase activities (P 1⁄4 NS compared with untreated cells) (Supplementary Figure 2). Incubation of NIH3T3 or W138 fibroblasts with increasing amounts of LAB027 dose-dependently increased the production of SOD (Po0.001 for NIH3T3 and Po0.001 for W138 with 4 mM LAB027) and glutathione reductase activities (Po0.001 for NIH3T3 and Po0.001 for W138 with 4 mM LAB027) versus untreated cells (Supplementary Figure 2) but had no effect on catalase levels.
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