Glucocorticoids (GCs) are commonly used in the clinic as a treatment for Chronic Lymphocytic Leukemia (CLL). The exact mechanism of GC action remains unclear and patients eventually develop resistance to this group of agents. Our findings show that GC-cytotoxicity in circulating CLL cells is caused by bioenergetic restriction resulting from the down-regulation of a key glycolytic enzyme, pyruvate kinase, muscle isozyme 2 (PKM2). Conversely, GCs were shown to promote fatty acid oxidation instead by up-regulating the expression of peroxisome proliferator activated receptor α (PPARα). These findings establish PPARα and fatty acid oxidation as novel mediators of GC resistance in CLL. Our findings also demonstrate that GCs enhance the cytotoxic effects of membrane-damaging agents such as ionophores and complement-mediated cytotoxicity. A clinically relevant agent known to intercalate in the cell membrane, Danazol was also found to have activity against CLL and can be combined safely with GCs for enhanced treatment efficacy.
Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/35695 |
Date | 17 July 2013 |
Creators | Tung, Stephanie Yee Ping |
Contributors | Spaner, David |
Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
Language | en_ca |
Detected Language | English |
Type | Thesis |
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