Structure-Activity Relationship and Mechanistic Studies on the Chemopreventive Activity of Dipyridamole and Its Analogues

<p>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 (<strong>DPM</strong>) showed potent chemopreventive activity against JB6 P⁺cells (tumor promotion sensitive). To probe the effects of <strong>DPM</strong> 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 <strong>DPM</strong> analogues. From this screening, Compound <strong>145</strong> was found to be more 30 times more potent than <strong>DPM </strong>(<strong>145</strong>, IC₅₀ = 0.12 µM; <strong>DPM</strong>, 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 <strong>DPM</strong>and analogues. Signaling pathways are pivotal in tumor promotion processes and were therefore tested for in the chemopreventive mechanism of <strong>DPM</strong>. 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,<strong> DPM</strong> 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. <strong>DPM</strong> 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 <strong>DPM</strong>. </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2008

Author dc:creator

• Grant, Ja’Wanda Shavon

Contributors dc:contributor

• John K. Buolamwini, Ph.D.

• chemoprevention
• dipyridamole
• MAP kinases
• nucleoside transporters
• Medicine and Health Sciences
• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/100

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1100