Potent Prostaglandin A1 Analogs That Suppress Tumor Cell Growth through Induction of p21 and Reduction of Cyclin E

Although the cyclopentenone prostaglandin A 1 (PGA 1 ) is known to arrest the cell cycle at the G 1 phase in vitro and to suppress tumor growth in vivo , its relatively weak activity limits its usefulness in cancer chemotherapy. In an attempt to develop antitumor drugs of greater potency and conspicuous biological specificity, we synthesized novel analogs based on the structure of PGA 1 . Of the newly synthesized analogs, 15- epi -Δ 7 -PGA 1 methyl ester (NAG-0092), 12- iso -Δ 7 -PGA 1 methyl ester (NAG-0093), and ent -Δ 7 -PGA 1 methyl ester (NAG-0022) possess a cross-conjugated dienone structure around the five-member ring with unnatural configurations at C(12) and/or C(15) and were found to be far more potent than native PGA 1 in inhibiting cell growth and causing G 1 arrest in A172 human glioma cells. These three analogs induced the expression of p21 at both RNA and protein levels in a time- and dose-dependent fashion. Kinase assays with A172 cells treated with these analogs revealed that both cyclin A- and E-dependent kinase activities were markedly reduced, although cyclin D1-dependent kinase activity was unaffected. Immunoprecipitation-Western blot analysis showed that the decrease in cyclin A-dependent kinase activity was due to an increased association of p21 with cyclin A-cyclin-dependent kinase 2 complexes, whereas the decrease in cyclin E-dependent activity was due to a combined mechanism involving reduction in cyclin E protein itself and increased association of p21. Thus, these newly synthesized PGA 1 analogs may prove to be powerful tools in cancer chemotherapy as well as in investigations of the structural basis of the antiproliferative activity of A series prostaglandins.