The polysialic acid mimetics idarubicin and irinotecan stimulate neuronal survival and neurite outgrowth and signal via protein kinase C

TY - JOUR

T1 - The polysialic acid mimetics idarubicin and irinotecan stimulate neuronal survival and neurite outgrowth and signal via protein kinase C

AU - Loers, Gabriele

AU - Astafiev, Steven

AU - Hapiak, Yuliya

AU - Saini, Vedangana

AU - Mishra, Bibhudatta

AU - Gul, Sheraz

AU - Kaur, Gurcharan

AU - Schachner, Melitta

AU - Theis, Thomas

N1 - Funding Information: The authors thank Eva Kronberg for excellent animal care, Markus Wolf for technical assistance and Noelle Messina for help with image acquisition. We are grateful to the National Institute of Health for funding this project as part of the R01 grant 4R01NS078385-05 and the Bundesministerium fuer Bildung und Forschung (BMBF) and Indian Council of Medical Research (ICMR) (Indo-German Research Project 10/050) for support. V.S. thanks the Council of Scientific and Industrial Research (CSIR) India for a Senior Research Fellowship. UGC, India grant under UPE and CPEPA schemes is acknowledged for providing infrastructure in Guru Nanak Dev University. The authors declare no conflict of interest. Publisher Copyright: © 2017 International Society for Neurochemistry

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Polysialic acid (PSA) is a large, negatively charged, linear homopolymer of alpha2-8-linked sialic acid residues. It is generated by two polysialyltransferases and attached to N- and/or O-linked glycans, and its main carrier is the neural cell adhesion molecule (NCAM). PSA controls the development and regeneration of the nervous system by enhancing cell migration, axon pathfinding, synaptic targeting, synaptic plasticity, by regulating the differentiation of progenitor cells and by modulating cell–cell and cell–matrix adhesions. In the adult, PSA plays a role in the immune system, and PSA mimetics promote functional recovery after nervous system injury. In search for novel small molecule mimetics of PSA that are applicable for therapy, we identified idarubicin, an antineoplastic anthracycline, and irinotecan, an antineoplastic agent of the topoisomerase I inhibitor class, as PSA mimetics using a competition enzyme-linked immunosorbent assay. Idarubicin and irinotecan compete with the PSA-mimicking peptide and colominic acid, the bacterial analog of PSA, for binding to the PSA-specific monoclonal antibody 735. Idarubicin and irinotecan stimulate neurite outgrowth and survival of cultured cerebellar neurons after oxidative stress via protein kinase C and Erk1/2 in a similar manner as colominic acid, whereas Fyn, casein kinase II and the phosphatase and tensin homolog are only involved in idarubicin and irinotecan-stimulated neurite outgrowth. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds irinotecan and idarubicin which trigger the same signaling cascades as PSA, thus introducing the possibility of retargeting these drugs to treat nervous system injuries. (Figure presented.).

AB - Polysialic acid (PSA) is a large, negatively charged, linear homopolymer of alpha2-8-linked sialic acid residues. It is generated by two polysialyltransferases and attached to N- and/or O-linked glycans, and its main carrier is the neural cell adhesion molecule (NCAM). PSA controls the development and regeneration of the nervous system by enhancing cell migration, axon pathfinding, synaptic targeting, synaptic plasticity, by regulating the differentiation of progenitor cells and by modulating cell–cell and cell–matrix adhesions. In the adult, PSA plays a role in the immune system, and PSA mimetics promote functional recovery after nervous system injury. In search for novel small molecule mimetics of PSA that are applicable for therapy, we identified idarubicin, an antineoplastic anthracycline, and irinotecan, an antineoplastic agent of the topoisomerase I inhibitor class, as PSA mimetics using a competition enzyme-linked immunosorbent assay. Idarubicin and irinotecan compete with the PSA-mimicking peptide and colominic acid, the bacterial analog of PSA, for binding to the PSA-specific monoclonal antibody 735. Idarubicin and irinotecan stimulate neurite outgrowth and survival of cultured cerebellar neurons after oxidative stress via protein kinase C and Erk1/2 in a similar manner as colominic acid, whereas Fyn, casein kinase II and the phosphatase and tensin homolog are only involved in idarubicin and irinotecan-stimulated neurite outgrowth. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds irinotecan and idarubicin which trigger the same signaling cascades as PSA, thus introducing the possibility of retargeting these drugs to treat nervous system injuries. (Figure presented.).

KW - cell survival

KW - idarubicin

KW - irinotecan

KW - neurite outgrowth

KW - polysialic acid

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U2 - https://doi.org/10.1111/jnc.14076

DO - https://doi.org/10.1111/jnc.14076

M3 - Article

C2 - 28542923

VL - 142

SP - 392

EP - 406

JO - Journal of neurochemistry

JF - Journal of neurochemistry

SN - 0022-3042

IS - 3

ER -