Effective Combination Therapy for Malignant Glioma with TRAIL-Secreting Mesenchymal Stem Cells and Lipoxygenase Inhibitor MK886

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. Cancer Res; 72(18); 4807-17. Ó2012 AACR.

Integrin α4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells

“…Previous studies have shown that BMSCs migrated directionally to glioma tissue (9,16). Accordingly, some studies applied BMSCs as the vector for targeted gene therapy against gliomas and obtained encouraging data (8,9). However, the mechanisms for the tropism of BMSCs towards glioma have yet to be fully elucidated and require further investigation.…”

“…Bone marrow mesenchymal stem cells (BMSCs) are a type of adult stem cells isolated from bone marrow. Due to their directional migration abilities towards gliomas after transplantation, they have been applied as the vectors of gene therapy against gliomas (7)(8)(9). However, the molecular mechanisms responsible for this migratory behavior have not been fully explained and require further investigation.…”

Mesenchymal stem cells as therapeutic agents and in gene delivery for the treatment of glioma

“…Thus, novel drugs are required that sensitize glioma cells to TRAIL-induced apoptosis, or new strategies are needed to overcome TRAIL resistance that can be combined with MSCs-TRAIL. Working toward these goals, different groups have explored various methods, including the use of TRAIL along with chemotherapeutic agents (Johnson et al, 2013;Kim et al, 2014), radiotherapy (Kim et al, 2010), lipoxygenase (Kim et al, 2012), and carbenoxolone (Yulyana et al, 2013). These methods have all had better therapeutic results than those using TRAIL alone.…”

Perspectives in Engineered Mesenchymal Stem/Stromal Cells Based Anti- Cancer Drug Delivery Systems

“…The application of this system (MSCs secreting TRAIL) has advantages over some of the other engineered MSC-delivery systems since there are almost no-detectable effects on non-cancerous tissues. Promising early results are obtained not only from the investigations with animal models, but also from clinical trials carried out currently [111][112][113][114].…”