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.

Effects of oxaliplatin and oleic acid Gc‐protein‐derived macrophage‐activating factor on murine and human microglia

“…At variance with its effects on neurons (Morucci et al, ), OA‐GcMAF does not appear to restore the decrease of cell viability induced by oxaliplatin, and, consistently, it does not increase cAMP or induce the expression of VEGF in BV‐2 or C13NJ cells. This study also demonstrates that the expression of B7‐2, a specific protein marker of microglial cell activation, increases in BV‐2 and C13NJ cells in the presence of oxaliplatin‐induced cell damage as well as after OA‐GcMAF treatment alone.…”

“…Therefore, this study was undertaken to assess these putative species‐specific differences in the pathophysiological responses of rodent and human microglial cells. In particular, the focus of this study is to compare the effects of oxaliplatin, a well‐known neurotoxic anticancer agent, and of oleic acid Gc‐protein‐derived macrophage‐activating factor (OA‐GcMAF), a protein inducing microglia activation (Morucci et al, ), on two microglial cell lines, murine BV‐2 cells and human C13NJ cells, in terms of cell viability, cAMP levels, microglia activation, and vascular endothelial growth factor (VEGF) expression. Oxaliplatin was chosen for its well‐studied mechanism of action and for its toxicity in neurons and glial cells.…”

“…Oxaliplatin was chosen for its well‐studied mechanism of action and for its toxicity in neurons and glial cells. OA‐GcMAF was chosen because previous findings (Morucci et al, ) have demonstrated that it is possible to reverse the neuronal damage inflicted by oxaliplatin significantly and to preserve neuronal viability, possibly through a cAMP/VEGF neuroprotective signaling pathway. To investigate the role of oxaliplatin and OA‐GcMAF in microglial and neuronal signalling further and to study the interactions between rodent and human cell types, we developed cocultures of murine microglial cells/human neurons (BV‐2/SH‐SY5Y) and human microglial cells/human neurons (C13NJ/SH‐SY5Y).…”

The experimental research on neuroplasticity in rats’ hippocampus subjected to chronic cerebral hypoperfusion and interfered by Modified Dioscorea Pills

“…In the case of cerebral ischemia, pyramidal neurons in CA1 zone of hippocampus can spontaneously regenerate [20]. GAP-43 is a pleiotropic cytokine, a key axonal and presynaptic component, which serves as a marker for axonal growth, motor neuron regeneration [21,22] and reconstruction of synapse [23]. It is highly expressed in nerve development and nerve injury [24].…”

Gc Protein-Derived Macrophage Activating Factor (GcMAF) and Autism: Do Clinical Results Require a Novel Interpretation?

“…It is worth noticing that, despite these obvious inconsistencies, GcMAF has been independently studied for about two decades by several research groups that reported consistent results in vitro and in vivo (for a recent review, see Ruggiero et al, 2016). My former research group, among others, has witnessed the effects of GcMAF derived from human blood on human mononuclear cells and on angiogenesis (Pacini et al, 2010;2012a), on human breast cancer cells (Pacini et al, 2012b;Thyer et al, 2013a) and on human neurons and glial cells (Morucci et al, 2015;Branca et al, 2015). We have also observed the clinical effects of GcMAF administration in the context of an integrated immunotherapeutic protocol for cancer (Ruggiero et al, 2014) and members of my former research group have described the effects of integrated GcMAF immunotherapy in diseases as diverse as cancer (Thyer et al, 2013b), chronic fatigue syndrome, multiple sclerosis, Lyme disease, amyotrophic lateral sclerosis, syphilis and autism (Thyer et al, 2013c).…”