ABSTRACT
Senegasaponins [senegin II (1), senegin III (2), senegin IV (3), senegasaponin a (4), and senegasaponin b (5)] from Polygala senega were re-discovered as selective anti-proliferative substances against human umbilical vein endothelial cells (HUVECs). Senegasaponins (1-5) showed anti-proliferative activity against HUVECs with IC(50) values in the range 0.6-6.2 µM, and the selective index was 7-100-fold in comparison with those for several cancer cell lines, while the desacyl mixture of senegasaponins (6) and tenuifolin (7) lost anti-proliferative activity, indicating that the 28-O-glycoside moiety and methoxycinnamoyl group were essential for the HUVEC-selective growth inhibition of senegasaponins. Senegin III (2) inhibited the vascular endothelial growth factor (VEGF)-induced in vitro tubular formation of HUVECs and basic fibroblast growth factor (bFGF)-induced in vivo neovascularization in the mouse Matrigel plug assay. Moreover, senegin III (2) suppressed tumor growth in the ddY mice s.c.-inoculated murine sarcoma S180 cells. The analysis of the action mechanism of senegin III (2) suggested that the induction of pigment epithelium-derived factor (PEDF) would contribute to the anti-angiogenic effects of senegasaponins.
Subject(s)
Polygala , Saponins , Triterpenes , Animals , Female , Humans , Mice , Cell Line , Cell Line, Tumor , Cell Movement/drug effects , Fibroblast Growth Factor 2/pharmacology , Immunoblotting , Molecular Structure , Neovascularization, Physiologic/drug effects , Polygala/chemistry , Saponins/chemistry , Saponins/pharmacology , Triterpenes/chemistry , Triterpenes/pharmacology , Vascular Endothelial Growth Factor A/pharmacologyABSTRACT
In the course of our search for anti-microbial agents against dormant Mycobacterium tuberculosis, halicyclamine A was re-discovered as a lead for anti-tuberculosis agent from a marine sponge of Haliclona sp. on the guidance of the constructed bioassay. Halicyclamine A showed growth inhibition against Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Ra with MICs in the range of 1.0-5.0microg/ml under both aerobic condition and hypoxic condition inducing dormant state. The growth-inhibitory activity of halicyclamine A was bactericidal, and halicyclamine A did not exhibit cross-resistance with the currently used anti-tuberculosis drugs of isoniazid, ethambutol, rifampicin, and streptomycin. Halicyclamine A has been isolated originally as one of the active constituents inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH). Then, in order to elucidate action-mechanism of halicyclamine A, we prepared IMPDH over-expressing strains of M. smegmatis. However, IMPDH was not target for halicyclamine A, because halicyclamine A showed same MIC value against the wild-type M. smegmatis and IMPDH over-expressing strains.
