Persistent Link:
http://hdl.handle.net/10150/294030
Title:
Targeting Copper: A Therapeutic Strategy In Lymphoma
Author:
Lee, Kristy
Issue Date:
2013
Publisher:
The University of Arizona.
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.
Embargo:
Release after 24-May-2015
Abstract:
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.
Type:
text; Electronic Dissertation
Keywords:
Cancer Biology
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Briehl, Margaret M.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleTargeting Copper: A Therapeutic Strategy In Lymphomaen_US
dc.creatorLee, Kristyen_US
dc.contributor.authorLee, Kristyen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.description.releaseRelease after 24-May-2015en_US
dc.description.abstractNon-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.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCancer Biologyen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorBriehl, Margaret M.en_US
dc.contributor.committeememberBriehl, Margaret M.en_US
dc.contributor.committeememberSmith, Catharine L.en_US
dc.contributor.committeememberTome, Margaret E.en_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.contributor.committeememberWondrak, Georgen_US
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