Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma
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Katarzyna Niedźwiecka1, Mariusz Dyląg1,*, Daria Augustyniak2, Grażyna Majkowska-Skrobek2, Magdalena Cal-Bąkowska1, Young H. Ko3, Peter L. Pedersen4, Andre Goffeau5, Stanisław Ułaszewski1,*
1Department of Genetics,Institute of Genetics and Microbiology, University of Wroclaw, Wroclaw, Poland
2Department of Pathogen Biology and Immunology, Institute of Genetics and Microbiology, University of Wroclaw, Wroclaw, Poland
3KoDiscovery, LLC, UM BioPark, Baltimore, MD, USA
4Departments of Biological Chemistry and Oncology and Sidney Kimmel Comprehensive Cancer Center (member at large), Johns Hopkins University School of Medicine, Baltimore, MD, USA
5Institut des Sciences de la Vie, Université Catholique de Louvain, Louvain-la-Neuve, Belgium
*These authors have contributed equally to this work
Mariusz Dyląg, email: firstname.lastname@example.org
Stanisław Ułaszewski, email: email@example.com
Keywords: 3-bromopyruvate (3BP), glutathione, buthionine sulfoximine, genes expression, fungi and MM cells
Received: January 05, 2016 Accepted: August 13, 2016 Published: August 25, 2016
In different fungal and algal species, the intracellular concentration of reduced glutathione (GSH) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3BP). Additionally, in the case of Cryptococcus neoformans cells 3BP exhibits a synergistic effect with buthionine sulfoximine (BSO), a known GSH depletion agent. This effect was observed when 3BP and BSO were used together at concentrations respectively of 4-5 and almost 8 times lower than their Minimal Inhibitory Concentration (MIC). Finally, at different concentrations of 3BP (equal to the half-MIC, MIC and double-MIC in a case of fungi, 1 mM and 2.5 mM for microalgae and 25, 50, 100 μM for human multiple myeloma (MM) cells), a significant decrease in GSH concentration is observed inside microorganisms as well as tumor cells. In contrast to the GSH concentration decrease, the presence of 3BP at concentrations corresponding to sub-MIC values or half maximal inhibitory concentration (IC50) clearly results in increasing the expression of genes encoding enzymes involved in the synthesis of GSH in Cryptococcus neoformans and MM cells. Moreover, as shown for the first time in the MM cell model, the drastic decrease in the ATP level and GSH concentration and the increase in the amount of ROS caused by 3BP ultimately results in cell death.
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