Date of Award

8-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Biological Sciences

Committee Chair/Advisor

RICE, CHARLES D

Committee Member

LARCOM , LYNDON L

Committee Member

SCOTT , THOMAS R

Committee Member

WHEELER , ALFRED P

Abstract

Indirubin is the active ingredient in the ancient herbal remedy, Danggui Longhui Wan, which is used as an anti-leukemic, anti-inflammatory, and detoxification treatment. Indirubin-3'-monoxime (IO) is the most widely studied of the indirubin derivatives. Most have been shown to inhibit cyclin-dependent kinases and glycogen synthase kinases, triggering cell cycle arrest and apoptosis with different levels of activity depending on the particular structure. These kinases inhibited by indirubin(s) play key roles in cellular proliferation and immune functions, therefore synthetic indirubins may have significant applications as therapeutic agents for cancer, inflammation, and neurological diseases.
Indirubin is also a potent aryl hydrocarbon receptor (AhR) agonist. The AhR is a cytosolic protein, which upon ligand binding is translocated to the nucleus and acts as a transcription factor for genes involved in drug metabolism, oxidative stress, and inhibitors of the cell cycle. Known anthropogenic ligands (PCBs, dioxins, PAHs etc.) are mutagenic, carcinogenic, and immunotoxic. In this study, I examined the effects of select indirubins on gene/protein expression profiles, AhR activation, and cellular functions in the mouse macrophage cell line RAW 264.7. Structure activity relationships (SAR) show that different derivatives of indirubin may differentially affect AhR activation, kinase inhibition, and/or other cellular functions, including intracellular killing of bacteria. The ultimate goal was to identify a synthetic indirubin derivative that would be beneficial to cancer and inflammation research without being overtly toxic.
From this research, Indirubin-3'-(2,3 dihydroxypropyl)-oximether) (E804), and 6-bromoindirubin-3-monoxime (BIO) were shown to be very potent AhR ligands with strong anti-inflammatory properties. This study also shows that E804 has more clinical promise than its more famous counterpart indirubin-3'-monoxime.

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Biology Commons

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