Date of Award

7-2020

Degree Type

Thesis

Degree Name

Master of Science

Department

Biology

Program

Integrated Biosciences

First Advisor/Chairperson

Robert Winn, Ph.D., Dean, College of Arts and Sciences

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and lethal form of adult brain cancer. The standard of care for GBM is maximal surgical resection followed by adjuvant treatment with the chemotherapeutic agent temozolomide (TMZ) and radiotherapy. O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein involved in TMZ resistance. Known as the Warburg effect, cancer cells will preferentially oxidize glucose to lactate in glycolysis. This less effective pathway of energy production means cancer cells must uptake significantly greater amounts of glucose to sustain physiological needs. One method that directly targets the bioavailability of glucose is fasting. Among other adaptations, fasting lowers systemic glucose levels and elevates ketone bodies like ß-hydroxybutyrate (ß-HB). This study sought to evaluate the effects of fasting in combination with TMZ on viability of GBM cell lines LN229 and T98G, and normal astroglial cell line SVG p12. Glucose restriction significantly enhanced the cytotoxic effects of TMZ in LN229 and T98G cells, while having no effect in SVG p12 cells. ß-HB in combination with TMZ potentiated the cytotoxicity of TMZ in LN229 and T98G cells, while reducing the cytotoxicity of TMZ in SVG p12 cells. Furthermore, both glucose restriction and ß-HB supplementation in combination with TMZ significantly decreased the expression of MGMT levels in T98G cells. Together, this initial evidence suggests fasting may be a useful method to selectively sensitize GBM cells to TMZ, while protecting normal cells. Future research is needed to further assess the efficacy of fasting as an adjuvant therapy in the treatment of GBM.

Access Type

Open Access

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