Abstract
By using the differential in level of oxidative status between normal and cancer cells, SuperOxide Dismutase (SOD) mimetics can have anti-tumor efficacy and prevent oxaliplatin-induced peripheral neuropathy. Our objective was to evaluate the neuroprotective efficacy of MAG, a new SOD mimic.In vitro, the effects of MAG alone or with oxaliplatin were studied on colon cancer cells (HT29 and CT26) and on normal fibroblast cells (NIH3T3). The cell viability (by crystal violet) as well as the production of reactive forms of oxygen and glutathione (by spectrofluorimetric assay) was measured. In vivo, efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. The effects on induced neurotoxicity were measured by specific behavioral Von Frey nociception, cold-plate tests, specific functional neuromuscular assay and electron microscopy.In vitro, MAG induced a production of hydrogen peroxide in all cells. At 24 h-incubation, MAG exhibits a cytotoxic activity in all cell lines. A cytotoxic additive effect of MAG and oxaliplatin was observed through oxidative burst. In vivo, oxaliplatin-treated mice associated with MAG did not counteract oxaliplatin’s antitumoral efficacy. After 4 weeks of treatment with oxaliplatin combined with MAG, behavioral and functional tests showed a decrease in peripheral neuropathy induced by oxaliplatin in vivo. Electron microscopy analyses on sciatic nerves revealed an oxaliplatin-induced demyelination which is prevented by the association of MAG to this chemotherapy.In conclusion, MAG prevents the appearance of sensitive axonal neuropathy and neuromuscular disorders induced by oxaliplatin without affecting its antitumor activity.
Highlights
Low levels of Reactive Oxygen Species (ROS) regulate cellular signaling and play an important role in normal cell proliferation by activating growth-related signaling pathways [1, 2]
H2O2 production was dose-dependently significantly increased with MAG in all cell lines (Figure 2A)
There were no significant differences in the production of O2− in all cell lines using DHE signature as a specific marker (Figure 2B)
Summary
Low levels of Reactive Oxygen Species (ROS) regulate cellular signaling and play an important role in normal cell proliferation by activating growth-related signaling pathways [1, 2]. Higher levels of ROS with inhibition of anti-oxidant systems compared to normal cells have been observed [3]. DNA damage induced by increased ROS production leads to genomic instability and cancer progression [4]. High levels of ROS appear to activate and modulate apoptosis when cells are under stress conditions by promoting pro-apoptotic signaling molecules including P53-induced apoptosis [5, 6]. Anti-cancer agents, such as oxaliplatin [7], have been shown to produce a burst in intracellular oxidative stress, that leads to cancer cells’ death through a higher sensitivity to the increased oxidative stress. The pathogenic events leading to the oxidative burst have been proven to be involved in the pathophysiology of the neurotoxicity induced by oxaliplatin [9]
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