Inhibiting Human Astrocytoma Growth:  Structure−Activity Relationships in Neurostatin Related Glycolipids

Romero‐Ramírez, Lorenzo; Nieto–Sampedro, Manuel

doi:10.1021/jm049816r

Cited by 12 publications

(9 citation statements)

References 10 publications

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“…Because neurostatin showed specificity for cells of astroglial lineage, it was a suitable candidate for treatment of CNS astrocytomas 356,357. However, the need to prepare and purify neurostatin from brain extracts, limited the availability and purity of the compound 357,377. Moreover, the O-acetyl group of neurostatin was very labile to hydrolysis under physiological pH conditions.…”

Section: Making Glioma Immunodetectablementioning

confidence: 99%

Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System

Nieto–Sampedro

Valle-Argos

Gómez-Nicola

et al. 2011

Clin Med Insights Oncol

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Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 μM or higher.At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step.

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Section: Making Glioma Immunodetectablementioning

confidence: 99%

Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System

Nieto–Sampedro

Valle-Argos

Gómez-Nicola

et al. 2011

Clin Med Insights Oncol

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“…Compared to other protocols described in the literature [12], [13], [14], [15], this method is easy, specific and gives high yields of O -acetylated ganglioside.…”

Section: Resultsmentioning

confidence: 94%

“…We [12], [13] and others [14], [15] have developed several synthetic methods for the enzymatic and chemical O -acetylation of commercial gangliosides, although the yields obtained were poor and the reactions led to many similar products that were very difficult to purify.…”

Section: Introductionmentioning

confidence: 99%

Specific Synthesis of Neurostatin and Gangliosides O-Acetylated in the Outer Sialic Acids Using a Sialate Transferase

et al. 2012

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Gangliosides are sialic acid containing glycosphingolipids, commonly found on the outer leaflet of the plasma membrane. O-acetylation of sialic acid hydroxyl groups is one of the most common modifications in gangliosides. Studies on the biological activity of O-acetylated gangliosides have been limited by their scarcity in nature. This comparatively small change in ganglioside structure causes major changes in their physiological properties. When the ganglioside GD1b was O-acetylated in the outer sialic acid, it became the potent inhibitor of astroblast and astrocytoma proliferation called Neurostatin. Although various chemical and enzymatic methods to O-acetylate commercial gangliosides have been described, O-acetylation was nonspecific and produced many side-products that reduced the yield. An enzyme with O-acetyltransferase activity (SOAT) has been previously cloned from the bacteria Campylobacter jejuni. This enzyme catalyzed the acetylation of oligosaccharide-bound sialic acid, with high specificity for terminal alpha-2,8-linked residues. Using this enzyme and commercial gangliosides as starting material, we have specifically O-acetylated the gangliosides’ outer sialic acids, to produce the corresponding gangliosides specifically O-acetylated in the sialic acid bound in alpha-2,3 and alpha-2,8 residues. We demonstrate here that O-acetylation occurred specifically in the C-9 position of the sialic acid. In summary, we present a new method of specific O-acetylation of ganglioside sialic acids that permits the large scale preparation of these modified glycosphingolipids, facilitating both, the study of their mechanism of antitumoral action and their use as therapeutic drugs for treating glioblastoma multiform (GBM) patients.

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“…8 Neurostatin was sensitive to deacetylation, producing inactive or even mitogenic gangliosides. 4,9 New synthetic inhibitory compounds in the low micromolar range, with higher chemical and biological stability, have been described recently by our group. 10,11 To find whether neurostatin and NF115 affected common biological pathways, we treated the U373-MG human glioblastoma line with both inhibitors and used DNA microarray screening to examine those genes whose expression was inhibited by both treatments.…”

Section: Introductionmentioning

confidence: 99%

“…6,7,12 Neurostatin inhibits proliferation of both primary astroblasts and glioma cells (both in rodents and humans) in culture, in both, defined medium and in the presence of 10% fetal calf serum. 9 NF115 (C 21 H 41 NO 9 ), on other hand, is an octyl N-acetylglucosaminide derivative with a pentaerythritol chain at position 6, obtained by a synthesis method that permitted preparation on a multigram scale. This compound inhibited the growth of a neuroectodermic tumor implanted in rats and caused the destruction of a cultured human astroblastoma obtained after surgical biopsy.…”

Section: Introductionmentioning

confidence: 99%