Date of Award

5-2016

Document Type

Thesis

Degree Name

Master of Science (MS)

Legacy Department

Biological Sciences

Committee Member

Charles D. Rice, PhD, Committee Chair

Committee Member

Yanzhang Wei, PhD

Committee Member

Vincent S. Gallicchio, PhD

Abstract

Glioblastomas are the most common malignant brain tumor, with an annual incidence of 6 in 100,000 people. Conventional treatment modalities, including chemotherapy and radiation, are toxic and cause a decrease in quality of life as the disease progresses. Several investigators have turned to pharmacologically active derivatives of herbal remedies as less-toxic alternatives. Indirubin, a dark red isomer of indigo, is known to be effective in treating chronic inflammation and some forms of cancer, and the mechanism is, in part, due to activity as a ligand for the transcription factor aryl hydrocarbon receptor (AhR). As with most AhR ligands, indirubin induces the CYP1 family of metabolizing enzymes, alters cell cycling, and can be active through the GSK-3β pathway. In recent years, bioavailable derivatives have been synthesized, including indirubin-3'-(2,3 dihydroxy-propyl)-oximether (E804). Several lines of research show that E804 has anti-angiogenic and anti-proliferative properties, and we previously demonstrated anti-inflammatory properties of E804. In this study, T98G human glioblastoma cells were treated with E804 to determine the degree of AhR activation, the secretion of both immunosuppressive and pro-inflammatory cytokines by the tumor cells, and the effects of those tumor secretions on macrophage polarization. E804 is potent inducer of CYP1B1 in T98G cells, has modest effects on TGFβ2 secretion, and suppresses VEGF at high does, while enhancing VEGF secretion at low doses. The secretion of IL-6 by T98G cells was only modestly affected at the highest treatment levels. The effects of supernatants derived from E804-treated T98G cells on macrophage indicate that E804 may polarize macrophages to the pro-tumor M2 phenotype. Overall, the results of this study indicate that E804 concentrations would need to be carefully monitored in a clinical application. Future studies should include an in vivo model of brain tumors to test the potential of E804 as a standalone, or adjuvant treatment for glioblastoma.

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