Abstract
BackgroundAntiangiogenic therapies are considered promising for the treatment of glioblastoma (GB). The non-collagenous C-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin, is an endogenous antiangiogenic polypeptide. Sustained enhanced expression of Vastatin was shown to inhibit tumour growth and metastasis in murine hepatocellular carcinoma models. In this study, we further explored the efficacy of Vastatin in the treatment of GB xenografts.MethodTreatment of Vastatin was carried out using a nanopolymer gene vector PEI600-CyD-Folate (H1). Antiangiogenic effect of Vastatin was tested in vitro by using co-culture system and conditioned medium. An orthotopic GB murine model was established to examine the in vivo therapeutic effect of Vastatin alone treatment and its combination with temozolomide.ResultsVastatin gene transfection mediated by H1 could target tumour cells specifically and suppress the proliferation of microvessel endothelial cells (MECs) through a paracrine inhibition manner. Enhancing Vastatin expression by intracerebral injection of H1-Vastatin significantly prolonged animal survival from 48 to 75 days in GB murine model, which was comparable to the effect of Endostatin, the most studied endogenous antiangiogenic polypeptide. The diminished presence of CD34 positive cells in the GB xenografts suggested that Vastatin induced significant antiangiogenesis. Moreover, a synergistic effect in extending survival was detected when H1-Vastatin was administered with temozolomide (TMZ) in GB chemoresistant murine models.ConclusionOur results suggest, for the first time, that Vastatin is an antiangiogenic polypeptide with significant potential therapeutic benefit for GB. H1-Vastatin gene therapy may have important implications in re-sensitizing recurrent GB to standard chemotherapeutic agents.
Highlights
Antiangiogenic therapies are considered promising for the treatment of glioblastoma (GB)
Vastatin gene transfection mediated by H1 could target tumour cells and suppress the proliferation of microvessel endothelial cells (MECs) through a paracrine inhibition manner
Enhancing Vastatin expression by intracerebral injection of H1-Vastatin significantly prolonged animal survival from 48 to 75 days in GB murine model, which was comparable to the effect of Endostatin, the most studied endogenous antiangiogenic polypeptide
Summary
Antiangiogenic therapies are considered promising for the treatment of glioblastoma (GB). The noncollagenous C-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin, is an endogenous antiangiogenic polypeptide. Sustained enhanced expression of Vastatin was shown to inhibit tumour growth and metastasis in murine hepatocellular carcinoma models. Through interfering with proliferation and metabolism of endothelial cells, Vastatin inhibited tumour growth and prevented metastasis in HCC-bearing rats [14]. A recombinant form of Vastatin, rhEDI-8 t, was discovered to be an angiogenesis inhibitor with potential therapeutic benefits for retinopathy-related neovascularization [15]. Since collagen VIII expression is known to be increased in brain tumours and participates in angiogenesis, we are interested in determining whether Vastatin could be used for the treatment of other hypervascular malignancies such as GB [16]
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