The native polyamines putrescine, spermidine, and spermine are small positively-charged molecules that can interact with negatively-charged macromolecules like DNA, RNA and proteins. These interactions aid in nucleic acid and protein conformational stability, thereby, making polyamines essential building blocks for cells. Polyamines are involved in various cellular functions including gene regulation, protein synthesis, and cell proliferation. Rapidly-proliferating cells, such as cancer cells, utilize high polyamine levels for cell growth. Targeting the polyamine addiction of cancers is a validated anti-cancer strategy. To achieve the maximal reduction of polyamine levels, polyamine blocking therapy (PBT) employs several compounds in combination. First, one can inhibit polyamine biosynthesis using difluoromethylornithine (DFMO). DFMO inhibits ornithine decarboxylase (ODC); a rate limiting enzyme required for the generation of putrescine. Unfortunately, inhibition of polyamine biosynthesis is often insufficient because cells escape DFMO pressure by upregulating polyamine import. To address this escape pathway, a polyamine transport inhibitor (PTI) is included with DFMO to reduce cell growth via PBT. There are two types of PTIs: polyamine-based and non-polyamine-based PTIs. Chapter 1 provides an overview of the field. In Chapter 2, we developed a novel polyamine-based PTI which is smaller and less toxic than the known PTIs and was equally potent when used in PBT. In Chapter 3, we identified the first non-polyamine-based, PTI (GW5074) that successfully reduced human cancer cell growth when dosed with DFMO. In Chapter 4, we discovered new DFMO adjunct agents which inhibit the far upstream element binding protein 1 (FUBP1). This type of PBT significantly reduced cancer cell growth and was directed at polyamine biosynthesis via a two-fold mechanism involving direct inhibition of polyamine biosynthesis (DFMO) and downregulation of upstream transcription factors like c-myc. In summary, we have described three categories of compounds that can be used as adjunctive agents for DFMO in anti-cancer therapies.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Doctoral Dissertation (Open Access)
Dobrovolskaite, Aiste, "Development of Adjunctive Agents for Difluoromethylornithine Anti-cancer Therapy" (2021). Electronic Theses and Dissertations, 2020-. 1323.