Inhibition of cell cycle progression through specific phase by pancratistatin derivatives

Pancratistatin derivatives, 1-O-(3-hydroxybutyryl)pancratistatin (HBP) and 1-O-(3-O-beta-D-glucopyranosylbutyryl)pancratistatin (GBP), showed strong cytostatic activity against rat embryo fibroblast 3Y1 at concentrations less than 1 microM. When the effect on cell cycle progression was examined in 3Y1 fibroblasts arrested at G0/G1 phase by serum deprivation, HBP, GBP, and pancratistatin inhibited the progression of 3Y1 fibroblasts from G0/G1 to S phase. In addition, when the effect on cell cycle progression was studied in 3Y1 fibroblasts synchronized at late G1/early S phases by treating with hydroxyurea, HBP blocked further progression through S phase, while GBP and pancratistatin did not affect the progression, but retarded it. On the other hand, when the effect of HBP and GBP on the progression was evaluated in promyelocytic leukemia HL-60RG cells synchronized at G0/G1 phase, the cells did not progress into S phase and accumulated in sub G0/G1 phase, which indicated apoptotic cells. These findings suggest that of Amaryllidaceae alkaloids, HBP blocks the progression of cell cycle at least at G0/G1 and S phases and GBP does at least at G0/G1 phase, resulting in apoptosis induction in tumor cells.