Date of Award

12-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

John K. Buolamwini, Ph.D.

Committee

Richard E. Lee, Ph.D. Duane Miller, Ph.D. David Nelson, Ph.D. Jie Zheng, Ph.D.

Keywords

chemoprevention, dipyridamole, MAP kinases, nucleoside transporters

Abstract

There is an escalating demand in the area of cancer prevention and control for the development of novel agents and molecular targets that have potential to reduce the incidence of cancer. In this study, the JB6 mouse epidermal cell-culture based transformation model was used in efforts to identify novel chemopreventive agents and targets. The nucleoside transport inhibitor dipyridamole (DPM) showed potent chemopreventive activity against JB6 P+cells (tumor promotion sensitive). To probe the effects of DPM structural features on its antitumor promotion activity, the soft-agar colony forming efficiency assay was used to screen an in-house library of structurally varied novel DPM analogues. From this screening, Compound 145 was found to be more 30 times more potent than DPM (145, IC50 = 0.12 µM; DPM, IC50 = 3.07 µM). Structure-activity relationships have been defined and will aid in the next phase of chemopreventive drug design. In regards to the antitumor promotion mechanism of DPM, a series of previously collected data are presented that support the novel hypothesis that nucleoside transporters may be potential chemoprevention targets involved in the antitumor promotion activity of DPMand analogues. Signaling pathways are pivotal in tumor promotion processes and were therefore tested for in the chemopreventive mechanism of DPM. In a previous study, the known chemoprevention target, AP-1, was studied for involvement in the antitumor promotion activity of DPM. Using a new AP-1-SEAP JB6 P+ reporter cell line, DPM was shown to inhibit TPA-induced AP-1 transactivation. Inhibition of AP-1 transactivation suggests the involvement of mitogen-activated protein kinase (MAPK) signaling pathways which are upstream effectors of AP-1 transactivation, and so the involvement of MAPKs was assessed in this study. DPM was shown to inhibit p38 MAPK activation in a dose-dependent manner, which suggests that this inhibition is a potential mechanism behind the chemopreventive activity of DPM.

DOI

10.21007/etd.cghs.2008.0114

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