Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Q. Ping Dou

Abstract

The ubiquitin-proteasome pathway is crucial to normal cellular function, and as such, has been extensively investigated as a potential target for cancer therapeutics. Many compounds have been tested for their proteasome inhibitory ability, including various small peptide aldehydes, and, following the success of cisplatin, several metal-containing complexes. The efficacy of these compounds in preclinical studies ultimately resulted in the development and approval of the first-in-class proteasome inhibitor bortezomib, the use of which, unfortunately, has been hindered by toxicity and resistance. These limitations have led to a massive push toward designing and developing new, less toxic proteasome inhibitors for clinical use.

The discovery more than twenty years ago that the heme-synthesis enzyme ä-aminolevulinic acid dehydratase (ALAD) possesses proteasome inhibitory activity revealed another potential approach for targeting the UPP in cancer. However, this discovery predated the initial investigation into proteasome inhibition as a therapeutic strategy, so a surprising lack of research into the relationship between ALAD and the proteasome exists. Therefore, further investigation into this relationship is necessary.

Taken together, these observations validate the proteasome as a viable chemotherapeutic target. Additionally, novel agents that target not only the proteasomal core, but also other factors involved in the pathway, including E3s like XIAP which are also critical components of the apoptotic cascade, as well as potential endogenous inhibitors like ALAD. The data presented in this dissertation suggest a novel interaction between the 20S proteasomal core and ALAD, which results in proteasome inhibition and tumor cell growth suppression, suggesting that targeting this relationship is a promising approach for cancer treatment. Additionally, a series of new metal-based complexes with various metal centers, including cobalt, gold, gallium and the copper chelator nitroxoline were shown to be potent inhibitors of the proteasome in several cancer cell lines and tumor xenograft models. Furthermore, proteasome inhibition was also revealed as a secondary mechanism of cell death for mercury-containing species. Finally, zinc chelation was explored as a strategy for inducing apoptosis via degradation of the E3 ligase X-linked inhibitor of apoptosis (XIAP). Collectively, these data confirm the potential of the UPP as an anticancer target and substantiate several factors within the pathway as viable druggable targets.

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