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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/193526 |
| Date | January 2010 |
| Creators | Jaramillo, Melba Concepcion Corrales |
| Contributors | Briehl, Margaret M., Briehl, Margaret M., Jacobson, Elaine, McDonagh, Paul, Rimsza, Lisa, Tome, Margaret E |
| 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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