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J.Health Sci., 57(4), 350-355, 2011
-Regular Article-
Cell-specific Synergic Effect of Cimicifugoside on Cytotoxicity of Methotrexate
Ayako Yawata,a, b Saki Kimura,b
Misato Matsushita,b Takehiro Mochizuki,b
Toshiyuki Chikuma,b Hiroshi Hojo,b
and Yasumitsu Ogra*, a, c
aLaboratory of Chemical Toxicology and Environmental Health,
bLaboratory of Hygienic Chemistry and
cHigh Technology Research Center, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
Cimicifugoside is a triterpenoid originating from the rhizomes of Cimicifuga simplex, and acts to inhibit the subcellular transport of nucleosides. Cimicifugoside, when used in combination with methotrexate, showed a cell-specific synergic effect on the promonocytic leukemia cell line U937, but not on the chronic myelogenetic leukemia cell line K562. Thymidine uptake was more severely inhibited by cimicifugoside in a dose-dependent fashion in U937 than in K562. The mRNA expression of one of the equilibrative Na+-independent nucleoside transporters, ENT2, was lower in U937 than in K562. This suggests that the thymidine uptake by ENT2 of U937 is more severely affected by cimicifugoside than that of K562, resulting in a decrease in DNA synthesis by methotrexate. In addition, cimicifugoside more efficiently stimulated the activity of thymidine kinase (TK) in K562 than in U937, suggesting that K562 resisted the decrease in DNA synthesis caused by the inhibition of nucleoside transporters. Cimicifugoside bifunctionally potentiated the cell-specific cytotoxicity of methotrexate by inhibiting ENT2 and activating TK.
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