Oxaliplatin-induced neuropathy: the preventive effect of a new super-oxide dismutase modulator
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Marie-Anne Guillaumot1, Olivier Cerles1, Hélène C. Bertrand2, Evelyne Benoit3,4, Carole Nicco1, Sandrine Chouzenoux1, Alain Schmitt5, Frédéric Batteux1,6, Clotilde Policar2 and Romain Coriat1,7
1 Département “Development, Reproduction and Cancer”, Institut Cochin, Paris Descartes Université, Sorbonne Paris Cité, INSERM U1016, Paris, France
2 Laboratoire des Biomolécules, LBM, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, Paris, France
3 Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), CEA de Saclay, Université Paris-Saclay, Gif-sur-Yvette, France
4 Institut des Neurosciences Paris-Saclay (Neuro-PSI), CNRS, UMR CNRS/Université Paris-Sud 9197, Université Paris-Saclay, Gif-sur-Yvette, France
5 Plateforme Imagerie Cellulaire, Microscopie électronique Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Paris, France
6 Service d’Immunologie, Centre Hospitalo-Universitaire Cochin AP-HP, Université Paris Descartes, Paris, France
7 Service de Gastro-Entérologie du Centre Hospitalo-Universitaire Cochin, APHP, Université Paris Descartes, Paris, France
Keywords: oxidative stress; super oxide dismutase; oxaliplatine; cancer cell; chemotherapy toxicities
Received: July 30, 2019 Accepted: September 10, 2019 Published: November 05, 2019
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.
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