Gnidilatimonoein from Daphne mucronata inhibits DNA synthesis in human cancer cell lines

The anticancer agents from plant sources usually exert their action through a wide range of mechanisms. As part of our studies of plants for new anticancer agents with emphasis on Thymelaeaceae family, we examined the cytotoxicity and anti-tumor activity of the water extract of D. mucronata leaves against induced breast tumor in rats. In the current study, we were interested to obtain some knowledge about the mode of action of the new compound. Cytotoxicity evaluation of gnidilatimonoein, the most active isolated diterpene ester from Daphne mucronata, revealed strong antiproliferative activity among several different human cancer cell lines (K562, CCRF-CEM, HL-60, MOLT-4 leukemia cell lines, and LNCaP-FGC-10 a prostate cancer cell line) and a mouse BALB/C fibrosarcoma cell line (WEHI-164). Using flow cytometry technique, it was found that treatment of the most responsive cells (K562) with gnidilatimonoein inhibited the progression of cells through G1 phase by almost 15% compared to the untreated cells. The population of the treated cells in the S and G2 phases was reduced by 8.3% and 5.4%, respectively. Based on the extent of [3H]-thymidine and [3H]-uridine incorporation into DNA and RNA, respectively, the major metabolic effects of gnidilatimonoein were found to be mainly on DNA and to a less extent on RNA synthesis. Additionally, the activity of inosine-5';-monophosphate dehydrogenase (IMPDH), under the effects of genidilatimonoein, was reduced in the treated cells by 44%. These data strongly suggest that the purine biosynthetic pathway is significantly affected by gnidilatimonoein. Our data indicates that gnidilatimonoein can inhibit the cell proliferation through DNA synthesis inhibition. These effects are mainly achieved through reduction of IMPDH activity.