Carbenoxolone enhances TRAIL-induced apoptosis through the upregulation of death receptor 5 and inhibition of gap junction intercellular communication in human glioma

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been used extensively in cancer therapy. However, more than half of glioblastoma multiforme are insensitive to the apoptotic effect of TRAIL. Improvement in therapeutic modalities that enhances the efficacy of TRAIL in glioma is muc...

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Published in:Stem cells and development Vol. 22; no. 13; p. 1870
Main Authors: Yulyana, Yulyana, Endaya, Berwini B, Ng, Wai H, Guo, Chang M, Hui, Kam M, Lam, Paula Y P, Ho, Ivy A W
Format: Journal Article
Language:English
Published: United States 01.07.2013
Subjects:
Animals
Apoptosis - drug effects
Brain Neoplasms - genetics
Brain Neoplasms - therapy
Carbenoxolone - pharmacology
Cell Line, Tumor
Connexin 43
Gap Junctions - metabolism
Gene Expression Regulation, Neoplastic
Glioma - genetics
Glioma - pathology
Glioma - therapy
Humans
Mesenchymal Stem Cell Transplantation
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - metabolism
Mice
Receptors, TNF-Related Apoptosis-Inducing Ligand - biosynthesis
Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics
Simplexvirus - genetics
TNF-Related Apoptosis-Inducing Ligand - biosynthesis
TNF-Related Apoptosis-Inducing Ligand - genetics
TNF-Related Apoptosis-Inducing Ligand - metabolism
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Up-Regulation
Xenograft Model Antitumor Assays
ISSN:1557-8534, 1557-8534
Online Access:Get more information
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Summary:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been used extensively in cancer therapy. However, more than half of glioblastoma multiforme are insensitive to the apoptotic effect of TRAIL. Improvement in therapeutic modalities that enhances the efficacy of TRAIL in glioma is much sought after. In this study, we combined the tumor selectivity of TRAIL and tumor-homing properties of mesenchymal stem cells (MSC) with gap junction (GJ) inhibitory effect of carbenoxolone (CBX) to target orthotopic glioma. MSC were engineered to express TRAIL (MSC-TRAIL) by incorporating the secretable trimeric form of TRAIL into a Herpes Simplex Virus (HSV) type I amplicon vector. Our results showed that combined treatment of MSC-TRAIL and CBX enhanced glioma cell death, especially in three primary human glioma isolates, of which two of those are marginally sensitive to TRAIL. CBX enhanced TRAIL-induced apoptosis through upregulation of death receptor 5, blockade of GJ intercellular communication, and downregulation of connexin 43. Dual arm therapy using TRAIL and CBX prolonged the survival of treated mice by ~27% when compared with the controls in an intracranial glioma model. The enhanced efficacy of TRAIL in combination with CBX coupled with the minimal cytotoxic nature of CBX suggested a favorable clinical usage of this treatment regimen.
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ISSN:1557-8534
1557-8534
DOI:10.1089/scd.2012.0529