title: Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP(5+), Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme.
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.
authors.affiliation: 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.
authors.forename: Yulyana
authors.initials: Y
authors.lastname: Yulyana
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Research Drive 281b/285 MSRB I, Box 3455, Durham, NC, 27710, USA.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: 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.|National Neuroscience Institute, Singapore, Singapore.
authors.forename: Ivy A W
authors.initials: IA
authors.lastname: Ho
authors.affiliation: 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.|National University of Singapore, Singapore, Singapore.
authors.forename: Kian Chuan
authors.initials: KC
authors.lastname: Sia
authors.affiliation: 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.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Newman
authors.affiliation: Department of Neurosurgery, National Neuroscience Institute, Singapore, Singapore.
authors.forename: Wai Hoe
authors.initials: WH
authors.lastname: Ng
authors.affiliation: Department of Orthopedics, Singapore General Hospital, Singapore, Singapore.
authors.forename: Chang Ming
authors.initials: CM
authors.lastname: Guo
authors.affiliation: 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.|Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore.
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Research Drive 281b/285 MSRB I, Box 3455, Durham, NC, 27710, USA. ibatinic@duke.edu.|Duke Cancer Institute, Duke University Medical Centre, Durham, NC, USA. ibatinic@duke.edu.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: 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.|Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore. cmrlyp@nccs.com.sg.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. cmrlyp@nccs.com.sg.
authors.forename: Paula Y P
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000819:agonists / Q000096:biosynthesis; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002229:Carbenoxolone / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D017629:Gap Junctions / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000819:agonists / Q000378:metabolism; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000494:pharmacology*; D009928:Organ Specificity; D018384:Oxidative Stress; D061251:Primary Cell Culture; D013438:Sulfhydryl Compounds / Q000819:agonists / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D013438:Sulfhydryl Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D002229:Carbenoxolone; D001205:Ascorbic Acid
keywords: Ascorbate; Carbenoxolone; Glioma; Manganese porphyrin; NAC; SOD mimic; TRAIL-modified human mesenchymal stem cells