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Glyoxalase 1 overexpression-associated multi-drug resistance in cancer chemotherapy
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Abbas, Hafsa (2020) Glyoxalase 1 overexpression-associated multi-drug resistance in cancer chemotherapy. PhD thesis, University of Warwick.
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WRAP_Theses_Abbas_2020.pdf - Submitted Version - Requires a PDF viewer. Download (4009Kb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b3711494
Abstract
Glyoxalase 1 (Glo1) overexpression is found in refractory tumours and this project aims to characterise the resistance to clinical anticancer drugs by Glo1 overexpression in the human HEK-293 tumour cell line in vitro and investigate druginduced increased methylglyoxal and related cytotoxicity as a likely cause.
HEK-293 cells had high Glo1 expression and activity that was increased up to 5-fold when stably transfected with a pIRES2-EGFP-GLO1 plasmid with respect to empty vector control using G-418. Dose-response studies determined the median growth inhibitory concentration and showed that Doxorubicin, Mitomycin C, Taxol, Methotrexate and Mechlorethamine had the highest Glo1-linked multi-drug resistance. There was drug-induced increased glycolysis and flux of methylgloxal formation in vitro. Transient transfection of GLO1 siRNA, the cell-permeable Glo1 inhibitor S-p-bromobenzylglutathione cyclopentyl diester, exogenous methylglyoxal and hypoxia potentiated the cytotoxicity of anti-tumour drugs and increased dicarbonyl stress. Stable isotopic LC-MS/MS analysis revealed that Mitomycin C enhanced glutathione (GSH) depletion whereas Mechlorethamine increased GSH levels. There were increased methylglyoxal levels in drug-treated HEK-293 cells in vitro.
Overall, decreasing Glo1 expression and activity increased MG toxicity and sensitivity to anti-tumour drugs. Anti-tumours drugs are not direct Glo1 inhibitors and may be influenced by unrecognised downstream signalling mechanisms on glycolysis and MG metabolism.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Library of Congress Subject Headings (LCSH): | Drug resistance in cancer cells, Glyoxalase, Tumors, Tumors -- Chemotherapy, Cancer -- Chemotherapy, Glycolysis | ||||
Official Date: | July 2020 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Thornalley, Paul J. ; Rabbani, Naila ; Mitchell, Daniel A. | ||||
Format of File: | |||||
Extent: | 231 leaves : illustrations | ||||
Language: | eng |
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