A Distinct Reactive Oxygen Species Profile Confers Chemoresistance in Glioma-Propagating Cells and Associates with Patient Survival Outcome

Koh, Lynnette W.H.; Koh, Geraldene R.H.; Ng, Felicia S.L.; Toh, Tan Boon; Sandanaraj, Edwin; Chong, Yuk Kien; Phong, Mark; Tucker‐Kellogg, Greg; Kon, Oi Lian; Ng, Wai Hoe; Ng, Ivan; Clément, Marie‐Véronique; Pervaiz, Shazib; Ang, Beng Ti; Tang, Carol

doi:10.1089/ars.2012.4999

Cited by 26 publications

(21 citation statements)

References 67 publications

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“…Furthermore, persistent elevation of ROS, in particular O 2 •− , has been implicated in enhanced resistance in glioma propagating cells. Koh and colleagues demonstrated that the ratio of O 2 •− to H 2 O 2 dictated the sensitivity of those cells [63]. Depletion of this ratio, i.e.…”

Section: Discussionmentioning

confidence: 99%

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Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP5+, Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme

Yulyana

Tovmasyan

et al. 2015

Stem Cell Rev and Rep

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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-PyP5+ (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.

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Section: Discussionmentioning

confidence: 99%

“…Depletion of this ratio, i.e. increase in H 2 O 2 levels, rendered these cells sensitive to drug-induced apoptosis [63]. Therefore, our strategy to increase intracellular H 2 O 2 levels by MnBuOE, enabling its cell death-promoting catalytic actions, may be advantageous as it can potentially target glioma stem cells.…”

Section: Discussionmentioning

confidence: 99%

Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP5+, Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme

Yulyana

Tovmasyan

et al. 2015

Stem Cell Rev and Rep

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“…The screening results in a list of compounds with a highly correlating gene expression pattern to that of the phenotype of interest, which has the potential to aid in finding a novel treatment for a disease or to identify novel pathways or genes involved in a complex biological process. To date, the CMap has been successfully used to identify compounds and combination therapies that show promise in the treatment of osteoarthritic pain (5), adenocarcinoma (6), kidney disease (7), gliomas (8), and NK cell neoplasms (9).…”

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confidence: 99%

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

Brum

Peppel

Leije

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h). Significantly regulated genes were analyzed in silico, and the Connectivity Map (CMap) was used to identify candidate bone stimulatory compounds. The signature of parbendazole matches the expression changes observed for osteogenic hMSCs. Parbendazole stimulates osteoblast differentiation as indicated by increased alkaline phosphatase activity, mineralization, and up-regulation of bone marker genes (alkaline phosphatase/ALPL, osteopontin/SPP1, and bone sialoprotein II/IBSP) in a subset of the hMSC population resistant to the apoptotic effects of parbendazole. These osteogenic effects are independent of glucocorticoids because parbendazole does not up-regulate glucocorticoid receptor (GR) target genes and is not inhibited by the GR antagonist mifepristone. Parbendazole causes profound cytoskeletal changes including degradation of microtubules and increased focal adhesions. Stabilization of microtubules by pretreatment with Taxol inhibits osteoblast differentiation. Parbendazole up-regulates bone morphogenetic protein 2 (BMP-2) gene expression and activity. Cotreatment with the BMP-2 antagonist DMH1 limits, but does not block, parbendazole-induced mineralization. Using the CMap we have identified a previously unidentified lineage-specific, bone anabolic compound, parbendazole, which induces osteogenic differentiation through a combination of cytoskeletal changes and increased BMP-2 activity.Connectivity Map | osteoblast | mesenchymal stem cell | cytoskeleton | osteoporosis

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“…confers a survival advantage, while a significant shift toward H 2 O 2 creates a permissive environment for death execution (84,144). For example, H 2 O 2 is known to suppress Wnt/b-catenin signaling, an important survival and growth pathway, through a variety of mechanisms, including targeting the interaction between nucleoredoxin and disheveled (Dvl) (52) and via oxidative modification of the zinc-coordinating cysteines of tankyrase resulting in its inactivation (78).…”

Section: Reactive Oxygen Species and Their Role In Cell Signalingmentioning

confidence: 99%

Cross Talk Between Cellular Redox State and the Antiapoptotic Protein Bcl-2

Pöhl

Agostino

Dharmarajan

et al. 2018

Antioxidants & Redox Signaling

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Based on its canonical functions, Bcl-2 has emerged as a potential druggable target. Small molecule inhibitors of Bcl-2 and/or other family members with similar function, as well as BH3 mimetics, are showing promise in the clinic. The emerging evidence for the noncanonical activity linked to cellular redox metabolism provides a novel avenue for the design and development of diagnostic and therapeutic strategies against cancers refractory to conventional chemotherapy by the overexpression of this prosurvival protein.

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A Distinct Reactive Oxygen Species Profile Confers Chemoresistance in Glioma-Propagating Cells and Associates with Patient Survival Outcome

Cited by 26 publications

References 67 publications

Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP5+, Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme

Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP5+, Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme

Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

Cross Talk Between Cellular Redox State and the Antiapoptotic Protein Bcl-2

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