Structural and mechanistic insights on the chemopreventive activity of dipyridamole and analogs Free

A149

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. The JB6 mouse epidermal cell-culture based transformation model has been used in our efforts to identify novel chemopreventive agents and targets. We have identified potent chemopreventive activity by dipyridamole (DPM) against JB6 P⁺ cells (tumor promotion sensitive). Dipyridamole inhibited TPA-induced tumor promotion with an IC₅₀ of 0.01 µM, while the known chemopreventive agent dehydroepiandosterone (DHEA) had an IC₅₀ of 1.0 µM in the same assay. The chemopreventive activity of an in-house library of DPM analogs has been tested using soft-agar colony forming efficiency. Structure activity relationship results from our studies will be presented. We have developed a new AP-1-SEAP JB6 P⁺ reporter cell line and successfully shown that DPM inhibits TPA-induced AP-1 transactivation. Inhibition of AP-1 transactivation suggests the involvement of mitogen-activated protein kinase (MAPK) signaling pathways in the mechanism of DPM antitumor promotion. The involvement of p38, Erk, and JNK in the antitumor promotion effect of potent DPM analogs will also be presented. Supported by funds from the National Cancer Institute, grant Nos. CA101856, CA105327 and CA125850.