Abstract
The apoptotic ligand TRAIL is believed to have promise as a cancer gene therapy, yet many types of cancer, including gliomas, have exhibited resistance to TRAIL-induced apoptosis. Here, we show that therapeutic combination of the lipoxygenase inhibitor MK886 and TRAIL-secreting human mesenchymal stem cells (MSC-TRAIL) provide targeted and prolonged delivery of TRAIL both in vitro and in orthotopic mouse models of glioma. Treatment of either TRAIL-sensitive or TRAIL-resistant human glioma cells with MK886 and MSC-TRAIL resulted in significantly enhanced apoptosis compared with each agent alone. MK886 effectively increased the sensitivity to TRAIL-induced apoptosis via upregulation of the death receptor 5 and downregulation of the antiapoptotic protein survivin in human glioma cell lines and in primary glioma cells. This regulation was accompanied by a substantial increase in caspase activation after combined treatment. Furthermore, in vivo survival experiments and imaging analysis in orthotopic xenografted mice showed that MSC-based TRAIL gene delivery combined with MK886 into the tumors had greater therapeutic efficacy than single-agent treatment. Together, our findings indicate that MK886 combined with MSC-based TRAIL gene delivery may represent a novel strategy for improving the treatment of malignant gliomas.
Highlights
Glioblastoma multiforme (GBM), the most common type of primary brain tumor, is highly aggressive and invasive
Most of the human glioma cell lines and GBM were resistant to TRAIL (Fig. 1A), and MK886 treatment exhibited a cytotoxic effect in a dose-dependent manner (Fig. 1B)
We examined the effect of MK886 on the TRAIL-induced apoptosis by Annexin V/PIbased flow cytometric analysis
Summary
Glioblastoma multiforme (GBM), the most common type of primary brain tumor, is highly aggressive and invasive. The median survival of GBM patients undergoing conventional treatment (i.e., surgery, radiotherapy, and chemotherapy) is 14.6 months for radiotherapy plus temozolomide and 12.1 months for radiotherapy alone [1]. The intrinsic high capacity of these tumors to invade and infiltrate the adjacent functional normal brain parenchyma, which hampers the complete surgical removal of tumors and results in tumor recurrence, and their resistance to most chemotherapy agents available currently are the main obstacles to GBM treatment [2]. Mesenchymal stem cells (MSC) have tumor-targeting properties, can be isolated and can be engineered with viral vectors, suggesting a potential clinical use in cancer gene therapy [3, 4]. The use of MSC-based gene therapy as an effective therapeutic gene delivery vehicle represents a prom-.
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