Macrophage-oriented cytotoxic activity of novel triterpene saponins extracted from roots of Securidaca inappendiculata.
It is recognized that macrophages in peripheral tissues often proliferate under pathological conditions such as tumors, inflammation and atherosclerosis. Because the growth state of macrophages is believed to be a factor regulating the pathological process of the diseases, substances that regulate macrophage growth or survival may be useful for disease control. In this paper, we identified the activity inhibiting macrophage growth in a hot water extract of roots of Securidaca inappendiculata. The extract markedly inhibited macrophage colony-stimulating factor (M-CSF/CSF-1)-induced growth of macrophages, whereas it exerted a less potent effect on growth of Concanavalin A (Con A)-stimulated thymocytes or M-CSF-stimulated bone marrow cells. The inhibition of macrophage growth was caused by a cytotoxic effect rather than a cytostatic effect. Cell death was due to the induction of apoptosis, as judged by staining with terminal deoxynucleotidyl transferase-mediated d-UTP nick end labelling (TUNEL). The cytotoxic activity seemed to be specific to peripheral macrophages; it showed a weak effect on the growth and survival of tumor cell lines including a macrophage-like cell line, J-774.1. Moreover, the saponin fraction induced apoptotic cell death of macrophages only when they were stimulated by M-CSF; it did not affect the viability of macrophages cultured without M-CSF or with granulocyte/macrophage-CSF. We determined the structures of the two active triterpene saponin compounds in the fraction, named securioside A and securioside B having a 3,4-dimethoxycinnamic group which is essential for the cell death-inducing activity. They are believed to be the primary compounds of new drugs for the treatment of pathological states in which macrophage proliferation occurs.
Yui
S
S
Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan. sat-yui@pharm.teikyo-u.ac.jp
Ubukata
K
K
Hodono
K
K
Kitahara
M
M
Mimaki
Y
Y
Kuroda
M
M
Sashida
Y
Y
Yamazaki
M
M
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010936:Plant Extracts / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D029608:Polygalaceae / Q000737:chemistry*; D012503:Saponins / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*
D007202:Indicators and Reagents; D010936:Plant Extracts; D012503:Saponins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014315:Triterpenes; C427044:securioside A; C427045:securioside B; D016173:Macrophage Colony-Stimulating Factor; C022616:thiazolyl blue