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Mesothelioma: HELP
Articles by Brian Cunniff
Based on 4 articles published since 2008

Between 2008 and 2019, Brian Cunniff wrote the following 4 articles about Mesothelioma.
+ Citations + Abstracts
1 Article Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. 2015

Cunniff, Brian / Newick, Kheng / Nelson, Kimberly J / Wozniak, Alexandra N / Beuschel, Stacie / Leavitt, Bruce / Bhave, Anant / Butnor, Kelly / Koenig, Andreas / Chouchani, Edward T / James, Andrew M / Haynes, Alexina C / Lowther, W Todd / Murphy, Michael P / Shukla, Arti / Heintz, Nicholas H. ·University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · University of Pennsylvania School of Medicine, Division of Pulmonary, Thoracic Oncology Research Laboratory, Philadelphia, PA, 19147, United States of America. · Wake Forest School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC, 27157, United States of America. · University of Vermont, College of Medicine, Department of Surgery, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · University of Vermont, College of Medicine, Department of Radiology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · University of Vermont, Department of Immunology medicine, 149 Beaumont Ave, Burlington, VT, 05405, United States of America. · Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. · Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom. ·PLoS One · Pubmed #26011724.

ABSTRACT: Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2--thioredoxin 2 (TRX2)--peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers. Due to the fact that activity of the PRX3 catalytic cycle dictates the rate of adduction by TS, immortalized and primary human mesothelial cells are significantly less sensitive to both compounds. Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS. Expression of catalase in shPRX3 mesothelioma cells restores defects in cell proliferation but not sensitivity to TS. In a SCID mouse xenograft model of human mesothelioma, administration of TS and GV together reduced tumor burden more effectively than either agent alone. Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies.

2 Article Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells. 2014

Cunniff, Brian / Wozniak, Alexandra N / Sweeney, Patrick / DeCosta, Kendra / Heintz, Nicholas H. ·Department of Biochemistry, University of Utah, Salt Lake City, UT, USA. · Department of Pathology, University of Vermont, College of Medicine, 149 Beaumont Avenue, Burlington, VT 05405, USA. · Department of Pathology, University of Vermont, College of Medicine, 149 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: Nicholas.Heintz@uvm.edu. ·Redox Biol · Pubmed #25462069.

ABSTRACT: Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial oxidants are produced in excess in cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in cancer cells has been shown to counteract oncogene-induced senescence and support tumor cell growth and survival making PRX3 a credible therapeutic target. Using malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either catalase or mitochondrial-targeted catalase, indicating high levels of hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism.

3 Article Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells. 2013

Cunniff, Brian / Benson, Kira / Stumpff, Jason / Newick, Kheng / Held, Paul / Taatjes, Douglas / Joseph, Joy / Kalyanaraman, Balaraman / Heintz, Nicholas H. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA. ·J Cell Physiol · Pubmed #23018647.

ABSTRACT: Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.

4 Article Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells. 2012

Newick, Kheng / Cunniff, Brian / Preston, Kelsey / Held, Paul / Arbiser, Jack / Pass, Harvey / Mossman, Brooke / Shukla, Arti / Heintz, Nicholas. ·Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, United States of America. ·PLoS One · Pubmed #22761781.

ABSTRACT: Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma.