The Modulation of Life and Death: Small Molecule Activators and Inhibitors of Necrotic and Apoptotic Pathways
Putt, Karson Stackhouse
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https://hdl.handle.net/2142/84836
Description
Title
The Modulation of Life and Death: Small Molecule Activators and Inhibitors of Necrotic and Apoptotic Pathways
Author(s)
Putt, Karson Stackhouse
Issue Date
2006
Doctoral Committee Chair(s)
Hergenrother, Paul J.
Department of Study
Biochemistry
Discipline
Biochemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Biochemistry
Language
eng
Abstract
The proper modulation of an individual cell's fate is critical to multi-cellular organisms. Manipulation of cellular fate through the use of small molecules can be instrumental in studying a cell's death pathways and for treating various pathologies. Therefore, the overarching theme that encompasses all of the following work is the identification of small molecule regulators of various proteins and using these small molecules to validate their target protein's importance in various disease models. The two major projects focus on the direct activation of procaspase-3 and the inhibition of poly(ADP-ribose) glycohydrolase (PARG). Through the development of high-throughput screens, a small molecule activator of procaspase-3 (PAC-1) and an inhibitor of PARG (PIP-1) were identified. PAC-1 was shown to potently induce apoptosis in mammalian cells in a manner directly proportional to the amount of procaspase-3 contained within those cells. As all normal cells contain procaspase-3, the upregulation of procaspase-3 in various cancers could provide for a selective killing in these cancerous cells by PAC-1. Indeed, PAC-1 was found to be selectively toxic to primary colon cancers expressing high levels of procaspase-3 when compared with normal adjacent tissue. PAC-1 was also able to retard the growth of tumors in several xenograft animal models of cancer. PIP-1 was identified as the first compound of a new class of non-intercalating, cell-permeable PARG inhibitors. The inhibition of PARG via PIP-1 was shown to be protective towards oxidative damage in cell culture and in Parkinson's disease models in cell lines and primary isolated neurons. PIP-1 readily penetrates the blood brain barrier and was able to protect dopaminergic neurons in a mouse model of Parkinson's disease. Through these studies, the direct activation of procaspases was validated as a new anti-cancer strategy and the inhibition of PARG was shown to be protective in models of Parkinson's disease.
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