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theses

Alteration of glucose metabolism is a unique feature for a majority of cancers. Cancer cells exhibit aerobic glycolysis also known as the Warburg effect even in the presence of oxygen. During this mode of glucose metabolism, a majority of pyruvate is converted to lactate rather than entering mitochondria for complete oxidation through oxidative phosphorylation. The functional importance of aerobic glycolysis to cancer cells is becoming clear. Basically, aerobic glycolysis prevents pyruvate from complete oxidation inside mitochondria. This shunts glycolytic intermediates to pathways for synthesis of NADPH and building blocks of macromolecules, which are required for cell growth and proliferation. Pyruvate entrance into mitochondria is enhanced via mitochondrial uncoupling, a process that permits proton influx through the mitochondrial inner membrane without generating ATP. Consequently, mitochondrial uncoupling stimulates “idle ” oxidation of acetyl-CoA, leading to complete oxidation of glucose. Thus, we hypothesize that safe mitochondrial uncouplers could be strong anticancer agents to inhibit the anabolic role of the Warburg effect. We utilized two approaches to address this hypothesis. First, we tested two mitochondrial uncoupler compounds, NEN (niclosamide ethanolamine) and oxyclozanide, on their metabolic effects and anti-cancer activities. We used metabolomics NMR to study the effect of mitochondrial uncoupling on glucose metabolism in colon cancer MC38 cells. We further examined the anti-cancer effect of NEN and oxyclozanide in cell models and hepatic metastasis of colon cancer in animal model. We found that mitochondrial uncoupling stimulates pyruvate influx to mitochondria and decreases various anabolic pathway activities. Moreover, mitochondrial uncouplers arrest cell cycle progression, inhibit cell proliferation and reduce clonogenicity. Furthermore, oral treatment with mitochondrial uncouplers diminishes hepatic metastasis of colon cancer cells transplanted intrasplenically in mice. Second, we tested MB1-47, a novel mitochondrial uncoupler with good pharmacokinetic and toxicological profiles, in preventing and treating pancreatic cancer. Our study demonstrated that MB1-47 is effective in inducing mitochondrial uncoupling in pancreatic cancer cells and inhibits the proliferation of multiple murine and human pancreatic cancer cell lines. In the tumor xenograft mouse models, oral MB1-47 treatment exhibits excellent activity in preventing tumor growth and metastasis. Our data support a unique approach for targeting cancer cell metabolism for cancer prevention and treatment and identified prototype compounds for this mechanism.

ETD_8749

Ph.D.

Includes bibliographical references

by Amer H. Al-Asadi

doi:10.7282/T3X92FQ4

ETD doctoral

The author owns the copyright to this work.