Non-Hodgkin lymphomas often arise at sites of chronic inflammation, exposing them to oxidative stress, or increased levels of reactive oxygen species (ROS). Increases in ROS are associated with tumor initiation, promotion and progression. Chronic exposure to ROS may promote the transformation of lymphocytes to lymphoma. Anti-apoptotic proteins such as Bcl-2 are commonly overexpressed in lymphoid malignancies. The protective function of Bcl-2 is partially dependent on its ability to regulate the redox environment. Adaptation to oxidative stress via the upregulation of anti-oxidant defense enzymes or upregulation of anti-apoptotic proteins appear to, in part, confer resistance to chemotherapeutics through their ability to regulate the redox environment. This suggests that using an agent to disrupt redox homeostasis has potential as a therapeutic strategy to circumvent these resistance mechanisms. The following studies examine the use of the copper chelator drug, ATN-224, to modulate the redox environment and circumvent the upregulation of anti-oxidant defense enzymes and anti-apoptotic proteins. These studies demonstrate that ATN-224 inhibits the primary anti-oxidant defense enzyme SOD1 and the redox-driven proton pump CcOX (complex IV in the electron transport chain). This inhibits the ability of SOD1 and CcOX to regulate the cellular and/or mitochondrial redox environment, respectively. ATN-224 treatment increases oxidative stress and induces peroxynitrite-dependent cell death. Furthermore, ATN-224 induces the release of AIF from the mitochondria, resulting in caspase-independent cell death. Collectively, these findings suggest that modulating the redox environment with ATN-224 has therapeutic potential in the treatment of non-Hodgkin lymphoma.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/294030 |
| Date | January 2013 |
| Creators | Lee, Kristy |
| Contributors | Briehl, Margaret M., Briehl, Margaret M., Smith, Catharine L., Tome, Margaret E., Vanderah, Todd W., Wondrak, Georg |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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