title: 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.
authors.affiliation: Postech-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seong Muk
authors.initials: SM
authors.lastname: Kim
authors.forename: Ji Sun
authors.initials: JS
authors.lastname: Woo
authors.forename: Chang Hyun
authors.initials: CH
authors.lastname: Jeong
authors.forename: Chung Heon
authors.initials: CH
authors.lastname: Ryu
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Lim
authors.forename: Sin-Soo
authors.initials: SS
authors.lastname: Jeun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D002722:Chlorobenzenes
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C060893:MK-886; D002722:Chlorobenzenes