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dc.contributor.authorHanberry, Bradley Scott
dc.date.accessioned2015-06-30T04:30:31Z
dc.date.available2015-06-30T04:30:31Z
dc.date.issued2014-12
dc.identifier.otherhanberry_bradley_s_201412_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/hanberry_bradley_s_201412_phd
dc.identifier.urihttp://hdl.handle.net/10724/31428
dc.description.abstractThe dichotomous effect of thiamine supplementation on cancer cell growth is characterized by growth stimulation at low doses and growth suppression at high doses. Unfortunately, how thiamine reduces cancer cell proliferation is currently unknown. Recent focuses on metabolic targets for cancer therapy have exploited the altered regulation of the thiamine-dependent enzyme pyruvate dehydrogenase (PDH). Cancer cells inactivate PDH through phosphorylation by overexpression of pyruvate dehydrogenase kinases (PDKs). Inhibition of PDKs exhibits a growth suppressive effect in many cancers. Recently it has been shown that the thiamine co-enzyme, thiamine pyrophosphate, can regulate the phosphorylation of PDH. Therefore, we hypothesize that high dose thiamine can normalize glycolysis in cancer cells leading to a cellular apoptosis. We have determined that high dose vitamin B1 reduces cell proliferation in cancer cell lines by a mechanism involving reduced PDH phosphorylation. Additionally we have established that thiamine homeostasis is up-regulated in cancer and in hypoxic microenvironments. Together these findings suggest that using high dose thiamine may provide an important targeting advantage directed towards altering the cancer metabolic phenotype.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectThiamine
dc.subjectTPK1
dc.subjectPyruvate Dehydrogenase
dc.subjectHypoxia
dc.subjectCell Metabolism
dc.subjectTransport
dc.subjectChemotherapy
dc.titleTargeting the cancer metabolic phenotype using high dose vitamin B1 therapy
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentPharmaceutical and Biomedical Sciences
dc.description.majorPharmaceutical and Biomedical Sciences
dc.description.advisorJason Zastre
dc.description.committeeJason Zastre
dc.description.committeeTamas Nagy
dc.description.committeeMandi Murph
dc.description.committeeRajgopal Govindarajan
dc.description.committeeRobert D. Arnold


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