Mechanism of cell cycle arrest by (8E,13Z,20Z)-strobilinin/(7E,13Z,20Z)-felixinin from a marine sponge Psammocinia sp.

Furanosesterterpenes, isolated from a marine sponge Psammocinia sp. have been reported to display significant cytotoxicity to some cancer cell lines. In this study, EZZ, an inseparable 1:1 mixture of (8E,3Z,20Z)-strobilinin and (7E,3Z,20Z)-felixinin, showed significant antiproliferative effect on human cervix carcinoma cell line (HeLa). Cell cycle analysis revealed that EZZ could arrest HeLa cells in S phase with a concomitant decrease in the cell population of G1 phase. By using simian virus (SV40) DNA in vitro replication system, we found that EZZ could inhibit DNA replication, which suggests that EZZ-induced S phase arrest might be the direct result of blocked DNA synthesis. Furthermore, low concentration of EZZ was found to be capable of significantly inhibiting the DNA cleavage by topoisomerase I (topo I) and reducing the polymerase alpha-primase (pol alpha-primase) activity, while the ssDNA binding activity of replication protein A (RPA) was less affected. Taken together, these results suggest that EZZ-induced cell cycle arrest in S phase correlate with the inhibition of DNA replication, and topo I and pol alpha-primase might be the two main target molecules.