Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP(5+), Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme

Yulyana Yulyana, Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
Artak Tovmasyan, Department of Radiation Oncology, Duke University Medical Center, Research Drive 281b/285 MSRB I, Box 3455, Durham, NC, 27710, USA.
Ivy A. Ho, Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
Kian Chuan Sia, Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
Jennifer P. Newman, Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
Wai Hoe Ng, Department of Neurosurgery, National Neuroscience Institute, Singapore, Singapore.
Chang Ming Guo, Department of Orthopedics, Singapore General Hospital, Singapore, Singapore.
Kam Man Hui, Bek Chai Heah Laboratory of Cancer Genomics, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore, Singapore, Singapore.
Ines Batinic-Haberle, Department of Radiation Oncology, Duke University Medical Center, Research Drive 281b/285 MSRB I, Box 3455, Durham, NC, 27710, USA. ibatinic@duke.edu.
Paula Y. Lam, Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. cmrlyp@nccs.com.sg.

Document Type

Article

Abstract

Glioblastoma multiforme is the most malignant tumor of the brain and is challenging to treat due to its highly invasive nature and heterogeneity. Malignant brain tumor displays high metabolic activity which perturbs its redox environment and in turn translates to high oxidative stress. Thus, pushing the oxidative stress level to achieve the maximum tolerable threshold that induces cell death is a potential strategy for cancer therapy. Previously, we have shown that gap junction inhibitor, carbenoxolone (CBX), is capable of enhancing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis in glioma cells. Since CBX is known to induce oxidative stress, we hypothesized that the addition of another potent mediator of oxidative stress, powerful SOD mimic MnTnBuOE-2-PyP(5+) (MnBuOE), could further enhance TRAIL-driven therapeutic efficacy in glioma cells. Our results showed that combining TRAIL + CBX with MnBuOE significantly enhances cell death of glioma cell lines and this enhancement could be further potentiated by CBX pretreatment. MnBuOE-driven cytotoxicity is due to its ability to take advantage of oxidative stress imposed by CBX + TRAIL system, and enhance it in the presence of endogenous reductants, ascorbate and thiol, thereby producing cytotoxic H2O2, and in turn inducing death of glioma cells but not normal astrocytes. Most importantly, combination treatment significantly reduces viability of TRAIL-resistant Asian patient-derived glioma cells, thus demonstrating the potential clinical use of our therapeutic system. It was reported that H2O2 is involved in membrane depolarization-based sensitization of cancer cells toward TRAIL. MnBuOE is entering Clinical Trials as a normal brain radioprotector in glioma patients at Duke University increasing Clinical relevance of our studies.

Keywords

Ascorbate, Carbenoxolone, Glioma, Manganese porphyrin, NAC, SOD mimic, TRAIL-modified human mesenchymal stem cells

Medical Subject Headings

Antineoplastic Agents (pharmacology); Apoptosis (drug effects); Ascorbic Acid (agonists, biosynthesis); Astrocytes (cytology, drug effects); Biomimetic Materials (chemical synthesis, pharmacology); Brain Neoplasms (drug therapy, genetics, metabolism, pathology); Carbenoxolone (pharmacology); Cell Line; Cell Line, Tumor; Cell Survival (drug effects); Drug Combinations; Drug Resistance, Neoplasm (drug effects); Drug Synergism; Gap Junctions (drug effects); Glioblastoma (drug therapy, genetics, metabolism, pathology); Humans; Hydrogen Peroxide (agonists, metabolism); Metalloporphyrins (chemical synthesis, pharmacology); Organ Specificity; Oxidative Stress; Primary Cell Culture; Sulfhydryl Compounds (agonists, metabolism); Superoxide Dismutase (chemistry); TNF-Related Apoptosis-Inducing Ligand (pharmacology)

Publication Date

2-1-2016

Publication Title

Stem cell reviews and reports

E-ISSN

2629-3277

Volume

12

Issue

1

First Page

140

Last Page

55

PubMed ID

26454429

Digital Object Identifier (DOI)

10.1007/s12015-015-9628-2

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