A new Manganese superoxide dismutase mimetic improves oxaliplatin induced neuropathy and global tolerance on mice.

Introduction: Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Oxidative stress is due to an imbalance between ROS or oxidants generation over the capability of the cell to elaborate an effective antioxidant response. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anion (O2•-) to hydrogen peroxide (H2O2). SOD mimetics can enhance the production of H2O2 and improve cytotoxic effect of chemotherapy. By using the differential in level of oxidative stress between normal and cancer cells, SOD mimetics can show an anti-tumoral effect and prevent oxaliplatin induced neuropathy. A new Pt(IV) conjugate prodrug called MAGOX, combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, was created. Methods In vitro, MAGOX anti-tumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3) treated with Mn1C1A alone, conjugates (MAG2OX, MAGOX mono-OH, MAGOX mono-OAc), oxaliplatin and vehicle. In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells. After tumor growth, Balb/c mice underwent randomization in 4 groups: vehicle, oxaliplatin, MAG2OX and Mn1C1A. Tumor size and volume were measured weekly. Oxaliplatin induced peripheral neuropathy was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including 4 items: weight loss, weariness, alopecia and diarrhea. Results: In vitro, the MnSODm associated with oxaliplatin and MAG2OX treatment induced a significant higher production of H2O2 in all cell lines, by itself. In the group of cell lines treated with the association of Mn1C1A and oxaliplatin and the group treated with MAG2OX, a significant improvement of the anti-tumoral efficacy compared to oxaliplatin alone was observed. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its anti-tumoral activity and MAG2OX had a lower anti-tumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased oxaliplatin induced peripheral neuropathy and also improved global clinical tolerance of oxaliplatin, therefore mice treated with Mn1C1A + oxaliplatin could receive more cumulated dose of oxaliplatin. Seric advanced oxidative protein products were higher in the Mn1C1A + oxaliplatin group versus oxaliplatin alone. PCR VEGF showed a higher VEGF RNA production in tumoral cells of mice treated with Mn1C1A than the other groups, as well as higher production of LC3 reflecting autophagy. Conclusion: A new Mn SOD mimetic called Mn1C1A associated with oxaliplatin showed superior anti tumoral activity than oxaliplatin, in vitro. The first Pt(IV) conjugate MAGOX had lower antitumoral activity, probably due to chemical instability issues. A new design is being evaluated. In vivo we observed a neuroprotective effect associated with a tolerance to oxaliplatin significantly improved, without impairing its antitumoral activity.