Persistent Link:
http://hdl.handle.net/10150/193526
Title:
Redox Regulation of Chemotherapy Response in Lymphoma
Author:
Jaramillo, Melba Concepcion Corrales
Issue Date:
2010
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.
Abstract:
Glucocorticoids are exploited for the treatment of hematological malignancies due to their ability to cause apoptosis in lymphoid cells. Innate and acquired resistance, however, limits their efficacy in the clinic. The mechanisms contributing to resistance are poorly understood. A better understanding of the critical events during glucocorticoid-induced apoptosis are needed in order to develop novel agents that will exploit these critical targets and improve the response to glucocorticoid-based therapies. Previously, using WEHI7.2 murine thymic lymphoma cells, our laboratory demonstrated that the levels of reactive oxygen species (ROS) increase during glucocorticoid-induced apoptosis signaling. WEHI7.2 cell variants with increased catalase exhibit increased resistance to glucocorticoids, suggesting that oxidative stress plays a role in glucocorticoid-induced apoptosis and that increasing the intracellular production of ROS may be a potential strategy for sensitizing lymphoma cells to glucocorticoid treatment. The following studies demonstrate that an increase in H₂O₂ is essential for lymphoma cells to undergo apoptosis and that the ability to remove cellular H₂O₂ protects the cells from glucocorticoid-mediated cell death. The redox-cycling agent, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin, increased glucocorticoid-induced oxidative stress in WEHI7.2 cells and sensitized the cells to glucocorticoid treatment. MnTE-2-PyP⁵⁺ glutathionylated NF-κB and inhibited its activity. Collectively, these findings suggest that manipulating the redox environment with MnTE-2-PyP⁵⁺ is a promising approach for lymphoma therapy.
Type:
text; Electronic Dissertation
Keywords:
Glucocorticoids; Lymphoma; Manganese Porphyrin; NF-kB; Oxidative Stress
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Cancer Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Briehl, Margaret M.
Committee Chair:
Briehl, Margaret M.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleRedox Regulation of Chemotherapy Response in Lymphomaen_US
dc.creatorJaramillo, Melba Concepcion Corralesen_US
dc.contributor.authorJaramillo, Melba Concepcion Corralesen_US
dc.date.issued2010en_US
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.abstractGlucocorticoids are exploited for the treatment of hematological malignancies due to their ability to cause apoptosis in lymphoid cells. Innate and acquired resistance, however, limits their efficacy in the clinic. The mechanisms contributing to resistance are poorly understood. A better understanding of the critical events during glucocorticoid-induced apoptosis are needed in order to develop novel agents that will exploit these critical targets and improve the response to glucocorticoid-based therapies. Previously, using WEHI7.2 murine thymic lymphoma cells, our laboratory demonstrated that the levels of reactive oxygen species (ROS) increase during glucocorticoid-induced apoptosis signaling. WEHI7.2 cell variants with increased catalase exhibit increased resistance to glucocorticoids, suggesting that oxidative stress plays a role in glucocorticoid-induced apoptosis and that increasing the intracellular production of ROS may be a potential strategy for sensitizing lymphoma cells to glucocorticoid treatment. The following studies demonstrate that an increase in H₂O₂ is essential for lymphoma cells to undergo apoptosis and that the ability to remove cellular H₂O₂ protects the cells from glucocorticoid-mediated cell death. The redox-cycling agent, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin, increased glucocorticoid-induced oxidative stress in WEHI7.2 cells and sensitized the cells to glucocorticoid treatment. MnTE-2-PyP⁵⁺ glutathionylated NF-κB and inhibited its activity. Collectively, these findings suggest that manipulating the redox environment with MnTE-2-PyP⁵⁺ is a promising approach for lymphoma therapy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectGlucocorticoidsen_US
dc.subjectLymphomaen_US
dc.subjectManganese Porphyrinen_US
dc.subjectNF-kBen_US
dc.subjectOxidative Stressen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorBriehl, Margaret M.en_US
dc.contributor.chairBriehl, Margaret M.en_US
dc.contributor.committeememberJacobson, Elaineen_US
dc.contributor.committeememberMcDonagh, Paulen_US
dc.contributor.committeememberRimsza, Lisaen_US
dc.contributor.committeememberTome, Margaret Een_US
dc.identifier.proquest11386en_US
dc.identifier.oclc752261252en_US
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