Vinorelbine and epirubicin share common features with polysialic acid and modulate neuronal and glial functions

Abstract

Polysialic acid (PSA), a large, linear glycan composed of 8 to over 100 α2,8-linked sialic acid residues, modulates development of the nervous system by enhancing cell migration, axon pathfinding, synaptic targeting and by regulating differentiation of progenitor cells. PSA also functions in developing and adult immune systems and is a signature of many cancers. In this study we identified vinorelbine, a semi-synthetic third generation vinca alkaloid, and epirubicin, an anthracycline and 4′-epimer of doxorubicin, as PSA mimetics. Similar to PSA, vinorelbine and epirubicin bind to the PSA-specific monoclonal antibody 735 and compete with the bacterial analogue of PSA, colominic acid in binding to monoclonal antibody 735. Vinorelbine and epirubicin stimulate neurite outgrowth of cerebellar neurons via the neural cell adhesion molecule (NCAM), via myristoylated alanine-rich C kinase substrate, and via fibroblast growth factor receptor, signaling through Erk pathways. Furthermore, the two compounds enhance process formation of Schwann cells and migration of cerebellar neurons in culture, and reduce migration of astrocytes after injury. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds vinorelbine and epirubicin, thus raising the possibility to retarget drugs used in treatment of cancers to nervous system repair.

The polysialic acid mimetics 5-nonyloxytryptamine and vinorelbine facilitate nervous system repair

“…5-NOT and vinorelbine were tested in a mouse model of spinal cord injury with immediate application after injury and directly into the lesion site. Compound concentrations used were slightly higher than those with highest impact on neurite growth and neuronal migration in vitro 26 27 and in the range of the PSA mimicking compound tegaserod 21 . Colominic acid was applied in parallel to compare the effects of PSA and the PSA mimicking compounds.…”

“…Compound concentrations used were slightly higher than those with highest impact on neurite growth and neuronal migration in vitro 2627 and in the range of the PSA mimicking compound tegaserod21. Colominic acid was applied in parallel to compare the effects of PSA and the PSA mimicking compounds.…”

“…Previous studies showed that 5-NOT, a known serotonin receptor 1B/1D agonist, and vinorelbine, a βIII-tubulin binding cytostatic drug approved for treatment of non-small cell lung cancer and breast cancer, can mimic PSA and enhance beneficial neuronal functions in vitro 26 27 . In the present study, we compared the compounds with the polysialic acid homolog colominic acid, in promoting functional recovery after spinal cord injury in mice.…”

“…To build upon the previous advances of identifying PSA mimetics with translational potential, we have screened a library of small organic molecules to identify novel PSA mimetics. This screen identified the compound 5-nonyloxytryptamine oxalate (5-NOT) and the FDA approved third generation vinca alkaloid vinorelbine as PSA mimetics, and both compounds stimulated neuronal functions beneficially in vitro 26 27 , thus encouraging the evaluation of their capacities in vivo .…”

5‐Nonyloxytryptamine oxalate–embedded collagen–laminin scaffolds augment functional recovery after spinal cord injury in mice

“…It is also considered the cardinal molecule for structural, functional, and synaptic plasticity of the adult nervous system . In order to exploit the vast therapeutic potential of PSA, previous studies have focused on the identification and development of peptide‐based or synthetic PSA mimetics . In a previous study, we observed ∼80% gain of locomotor function in mice after 8 weeks of a single intraoperative application of a synthetic PSA mimetic 5‐nonyloxytryptamine (5‐NOT) following spinal cord compression injury (SCCI) …”