Design of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia-Induced Transcription

Persistent Link:
http://hdl.handle.net/10150/194826
Title:
Design of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia-Induced Transcription
Author:
Block, Katherine M.
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:
Because of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics.The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1α (hypoxia inducible factor-1α) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1α. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1α also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1α and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response.The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.
Type:
text; Electronic Dissertation
Keywords:
Angiogenesis; Cancer; ETP; HIF; PARG; PARP
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmaceutical Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Jacobson, Myron
Committee Chair:
Jacobson, Myron

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleDesign of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia-Induced Transcriptionen_US
dc.creatorBlock, Katherine M.en_US
dc.contributor.authorBlock, Katherine M.en_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.abstractBecause of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics.The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1α (hypoxia inducible factor-1α) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1α. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1α also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1α and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response.The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAngiogenesisen_US
dc.subjectCanceren_US
dc.subjectETPen_US
dc.subjectHIFen_US
dc.subjectPARGen_US
dc.subjectPARPen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorJacobson, Myronen_US
dc.contributor.chairJacobson, Myronen_US
dc.contributor.committeememberRegan, Johnen_US
dc.contributor.committeememberSmith, Catharineen_US
dc.contributor.committeememberWondrak, Georgen_US
dc.contributor.committeememberMaggiora, Gerryen_US
dc.identifier.proquest10829en_US
dc.identifier.oclc659753707en_US
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