Enhanced expression of proapoptotic and autophagic proteins involved in the cell death of glioblastoma induced by synthetic glycans

Laboratory investigation

Ahmad Faried M.D., Ph.D.1, Muhammad Zafrullah Arifin M.D., Ph.D.1, Shogo Ishiuchi M.D., Ph.D.2, Hiroyuki Kuwano M.D., Ph.D.3, and Shin Yazawa Ph.D.3,4
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  • 1 Department of Neurosurgery, Faculty of Medicine, Universitas Padjadjaran–Dr. Hasan Sadikin Hospital, Bandung, Indonesia;
  • | 2 Department of Neurosurgery, Faculty of Clinical Medicine, the University of Ryukyus, Nakagami-gun, Okinawa;
  • | 3 Department of General Surgical Science, Faculty of Medicine, Gunma University, Maebashi; and
  • | 4 Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan
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Object

Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo.

Methods

The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans.

Results

Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans.

Conclusions

These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

Abbreviations used in this paper:

Akt = protein kinase B; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CPI = cell proliferation inhibition; HP-β-CD = hydroxypropyl-β-cyclodextrin; GalβChol = d-galactose β cholestanol; GChol = GlcNAcβChol; GGChol = GlcNAcβ1,3 GalβChol; GlcNAcβ1,3 = N-acetyl-d-glucosamine β1,3; GluR1 = glutamate receptor 1; GluR4 = glutamate receptor 4; HO342 = Hoechst 33342; MDC = monodansylcadaverine; mTOR = mammalian target of rapamycin; PARP = poly (adenosine diphosphate-ribose) polymerase; PI3K = phosphatidylinositol 3-kinase; Z-VAD-FMK = benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone.

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