{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/78558"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/78558","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Targeting Polyamine Metabolism in Prostate Cancer: Determining the Role of Reactive Oxygen Species in the Response to Treatment with a Novel Combination of the Polyamine Analogue, BENSpm, and the MTAP Inhibitor, MTDIA","abstract":"M.S.","abstract_html":"M.S.","abstract_has_math":false,"creators":["Pellerite, Anthony"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Smiraglia, Dominic","Roswell Park"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-10-26T02:55:30Z","date_published":"2018-10-26T02:55:30Z","updated_at":"2026-07-27T19:05:12Z","subjects":["molecular biology","cellular biology","biology","cancer sciences"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/78558","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Smiraglia, Dominic","Roswell Park"]},{"key":"dc:creator","label":"Author","values":["Pellerite, Anthony"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-10-26T02:55:30Z","2018","2018-08-08 13:04:31"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["molecular biology","cellular biology","biology","cancer sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/78558"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["M.S.","Prostatic luminal epithelial cells secrete polyamines into the lumen at a uniquely high rate. This leads to a metabolic demand to replenish metabolites used up during that process. To support this, there is increased flux through connecting metabolic pathways which makes the cells vulnerable to disruption of those pathways. Spermidine/spermine N1-acetyltransferase (SSAT) is a major driver of this flux as it acetylates polyamines prior to their secretion. To overcome the strain put on the system due to increased polyamine biosynthesis, cells recycle the one-carbon unit, 5’-methythioadenosine (MTA), back into the methionine cycle to replenish S-adenosylmethionine (SAM) pools via the methionine salvage pathway (MSP). The rate-limiting enzyme of the MSP is methythioadenosine phosphorylase (MTAP). We target this metabolic vulnerability through a novel combination approach. To exacerbate the enhanced polyamine metabolism of these cells, we use the polyamine analogue N1,N11-bisethylnorspermine (BENSpm) which binds and stabilizes SSAT. We also utilize Methylthio-DaDMe-Immucillin-A (MTDIA), a transition state analogue inhibitor of MTAP. Our combination induces a metabolic crisis resulting in an anti-proliferative effect which progresses into a cytotoxic effect over prolonged treatment. Another way cells can relieve stress of the increased polyamine biosynthesis is through polyamine catabolism. Spermine oxidase (SMOX) converts acetylated spermine into its precursor, spermidine. Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX) cleaves acetylated polyamines into their non-acetylated precursors. These reactions generate reactive oxygen species (ROS) which can be toxic to the cell at certain thresholds, as well as impact downstream transcription of genes involved in redox balance. We observed that the combination of BENSpm and MTDIA upregulates the activity and transcription of the catabolic enzymes. This leads to increased levels of ROS accumulation and decreased levels of proliferation in both androgen-sensitive and androgen-independent cells. We also determined that the ROS accumulated in response to our combination treatment was responsible for the anti-proliferative effect. Overexpression of thioredoxin reductase 2 (TXRND2), an enzyme responsible for clearing mitochondrial ROS, reduced levels of intracellular hydrogen peroxide (H2O2) and rescued proliferation in the androgen-independent setting. While TXNRD2 overexpression failed to reduce intracellular H2O2 or rescue proliferation in androgen sensitive cells treated with our combination therapy, when treated with hydrogen peroxide at low concentrations, we observed partial ROS reduction and rescue of proliferation. We also observed that both our combination treatment and androgen status regulate the cellular response to oxidative stress via nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) transcription and transcription of its targets in the antioxidant response axis."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Targeting Polyamine Metabolism in Prostate Cancer: Determining the Role of Reactive Oxygen Species in the Response to Treatment with a Novel Combination of the Polyamine Analogue, BENSpm, and the MTAP Inhibitor, MTDIA"]}]}],"canonical_facts":{"dc:contributor":["Smiraglia, Dominic","Roswell Park"],"dc:creator":["Pellerite, Anthony"],"dc:date":["2018-10-26T02:55:30Z","2018","2018-08-08 13:04:31"],"dc:description":["M.S.","Prostatic luminal epithelial cells secrete polyamines into the lumen at a uniquely high rate. This leads to a metabolic demand to replenish metabolites used up during that process. To support this, there is increased flux through connecting metabolic pathways which makes the cells vulnerable to disruption of those pathways. Spermidine/spermine N1-acetyltransferase (SSAT) is a major driver of this flux as it acetylates polyamines prior to their secretion. To overcome the strain put on the system due to increased polyamine biosynthesis, cells recycle the one-carbon unit, 5’-methythioadenosine (MTA), back into the methionine cycle to replenish S-adenosylmethionine (SAM) pools via the methionine salvage pathway (MSP). The rate-limiting enzyme of the MSP is methythioadenosine phosphorylase (MTAP). We target this metabolic vulnerability through a novel combination approach. To exacerbate the enhanced polyamine metabolism of these cells, we use the polyamine analogue N1,N11-bisethylnorspermine (BENSpm) which binds and stabilizes SSAT. We also utilize Methylthio-DaDMe-Immucillin-A (MTDIA), a transition state analogue inhibitor of MTAP. Our combination induces a metabolic crisis resulting in an anti-proliferative effect which progresses into a cytotoxic effect over prolonged treatment. Another way cells can relieve stress of the increased polyamine biosynthesis is through polyamine catabolism. Spermine oxidase (SMOX) converts acetylated spermine into its precursor, spermidine. Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX) cleaves acetylated polyamines into their non-acetylated precursors. These reactions generate reactive oxygen species (ROS) which can be toxic to the cell at certain thresholds, as well as impact downstream transcription of genes involved in redox balance. We observed that the combination of BENSpm and MTDIA upregulates the activity and transcription of the catabolic enzymes. This leads to increased levels of ROS accumulation and decreased levels of proliferation in both androgen-sensitive and androgen-independent cells. We also determined that the ROS accumulated in response to our combination treatment was responsible for the anti-proliferative effect. Overexpression of thioredoxin reductase 2 (TXRND2), an enzyme responsible for clearing mitochondrial ROS, reduced levels of intracellular hydrogen peroxide (H2O2) and rescued proliferation in the androgen-independent setting. While TXNRD2 overexpression failed to reduce intracellular H2O2 or rescue proliferation in androgen sensitive cells treated with our combination therapy, when treated with hydrogen peroxide at low concentrations, we observed partial ROS reduction and rescue of proliferation. We also observed that both our combination treatment and androgen status regulate the cellular response to oxidative stress via nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) transcription and transcription of its targets in the antioxidant response axis."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/78558"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["molecular biology","cellular biology","biology","cancer sciences"],"dc:title":["Targeting Polyamine Metabolism in Prostate Cancer: Determining the Role of Reactive Oxygen Species in the Response to Treatment with a Novel Combination of the Polyamine Analogue, BENSpm, and the MTAP Inhibitor, MTDIA"],"dc:type":["Thesis","Text"]},"updated_at":"2026-07-27T19:05:12Z"}