title: Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin.
abstract: Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce the dual effect of reduction of oxaliplatin-induced neurotoxicity, together with possible synergism in the overall anticancer effect.
authors.affiliation: Departments of aExperimental and Clinical Medicine bClinical and Biomedical Experimental Sciences cNeurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Firenze, Firenze, Italy dImmuno Biotech Ltd, St. Peter Port, Guernsey, Channel Islands, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Morucci
authors.forename: Jacopo J V
authors.initials: JJ
authors.lastname: Branca
authors.forename: Massimo
authors.initials: M
authors.lastname: Gulisano
authors.forename: Marco
authors.initials: M
authors.lastname: Ruggiero
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Paternostro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pacini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Pacini
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D051940:B7-2 Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D006801:Humans; D016215:Macrophage-Activating Factors / Q000494:pharmacology*; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000494:pharmacology*
chemical_list: C112986:AIF1 protein, human; D000970:Antineoplastic Agents; D051940:B7-2 Antigen; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D019922:GAP-43 Protein; D016215:Macrophage-Activating Factors; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D009944:Organoplatinum Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014809:Vitamin D-Binding Protein; C101908:vitamin D-binding protein-macrophage activating factor; D000077150:Oxaliplatin; D000242:Cyclic AMP