Date of Award

2014

Document Type

Thesis

Department

Biology

First Advisor

Dr. Lori Hensley

Second Advisor

Dr. Marty Perry

Third Advisor

Dr. Chris Mortenson

Abstract

Ewing's Sarcoma (ES) is a malignant cancer characterized by the formation of tumors in bones or soft tissues of primarily children and young adults. With the tendency for local recurrence and metastasis, ES is an aggressive cancer. The treatment is intensive and often yields poor long-term results. A cannabinoid derived compound, ajulemic acid (AJA), has shown strong cytotoxic effects on ES cell lines. The synthetic compound is unlike its cannabinoid counterpart tetrahydrocannabinol by lacking psychotropic effects. To investigate the possibility of utilizing AJA as a chemotherapeutic drug, the biochemical mechanism behind the cytotoxic effects of AJA needs further research. A proposed mechanism includes the binding of AJA to nuclear receptors in ES cells such as peroxisome proliferator-activated receptor (PPAR-y). While past studies have provided great evidence for AJA binding to PPAR-y, data from western blot analysis indicate the absence of PPAR-y receptors in ES cells. Computational analysis was employed to find 3D structural analogs of PPAR-y by using SMAP software program to generate a list of such analogs with PPAR-y as the template. One of the receptors most similar to PPAR-y was vitamin D3 receptor (VD3R). Next, Surflex Dock, from Tripos Inc. Sybyl-X 1.3 program, measured how well AJA docked with VD3R by calculating total scores, crash score, C-scores, and global C-scores. Total scores greater than 7, and both C-scores and global C-scores of 4-5 indicated a good fit. The nest step in determining, if VD3R could be an important receptor through which AJA is working, is to investigate its expression in ES cells and effects on cell visibility which appropriate antagonists are used.

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