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.
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Authors | Seong Muk Kim, Ji Sun Woo, Chang Hyun Jeong, Chung Heon Ryu, Jung Yeon Lim, Sin-Soo Jeun |
Journal | Cancer research
(Cancer Res)
Vol. 72
Issue 18
Pg. 4807-17
(Sep 15 2012)
ISSN: 1538-7445 [Electronic] United States |
PMID | 22962275
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Indoles
- RNA, Small Interfering
- TNF-Related Apoptosis-Inducing Ligand
- MK-886
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Topics |
- Animals
- Antineoplastic Agents
(administration & dosage)
- Blotting, Western
- Brain Neoplasms
(drug therapy, metabolism)
- Cell Line, Tumor
- Combined Modality Therapy
- Flow Cytometry
- Genetic Therapy
(methods)
- Glioma
(drug therapy, metabolism)
- Humans
- Immunohistochemistry
- Indoles
(administration & dosage)
- Male
- Mesenchymal Stem Cell Transplantation
(methods)
- Mesenchymal Stem Cells
(metabolism)
- Mice
- Mice, Nude
- RNA, Small Interfering
- TNF-Related Apoptosis-Inducing Ligand
(metabolism)
- Transfection
- Xenograft Model Antitumor Assays
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