Year of Award

2018

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Howard Beall

Commitee Members

Andrij Holian, Nicholas Natale, Sarjubhai Patel, Jesse Hay

Keywords

antitumor, c-MYC, DNA, electron transport chain, mitochondria, quadruplex

Publisher

University of Montana

Abstract

Cancer is a disease characterized by the abnormal proliferation of cells in the body. For many forms of cancer, there remain only limited and often ineffective treatment options available. Treatment of cancer is problematic for several reasons that include the difficulty in establishing molecular targets, finding interventions that cause selective toxicity to cancer cells, and the uniform capability of cancer cells to evade apoptosis. To address this, new strategies must be employed that take advantage of novel mechanisms of action to develop better therapies. The goal of this research is to aid in this effort through the study of emerging targets and antitumor agents. In these studies, we characterize the structure of an important target in the field of anticancer drug design, the quadruplex formed in the human c-MYC promoter region. The oncogene c-MYC is dysregulated or overexpressed in approximately 70% of human cancers and contributes to many survival pathways used by cancer cells to evade apoptosis. Stabilization of the c-MYC promoter quadruplex has been shown to reduce c-MYC expression and cause apoptosis in tumor cells. We also examine the mechanisms of action of two novel classes of antitumor agents, the anthracenyl isoxazole amides (AIMs) and a group of 5,8-quinolinedione analogs. We demonstrate interactions of the AIMs with quadruplex-forming sequences found in human telomeres, the c-MYC promoter, and mitochondrial DNA. Additionally, we provide evidence that the AIMs can inhibit the electron transport chain of mitochondria, specifically Complex II. Further, we show that treatment with the AIMs causes damage to mitochondrial DNA and loss of the mitochondrial membrane potential, leading to the intrinsic pathway of apoptosis in human glioblastoma cells. We also show a novel set of 5,8-quinolinedione analogs have potent antitumor activity in human breast cancer cells not related to their suitability as substrates for the NQO1-reductase that is often overexpressed in cancer. Together, this work has provided new insights to the field of anticancer drug discovery through characterization of an important target, the c-MYC promoter quadruplex, and through analysis of two novel classes of antitumor compounds, the AIMs and the 5,8-quinolinediones.

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© Copyright 2018 Sascha Christian LaMotte Stump