Triterpene Glycosides from Cimicifuga FoetidaRegulate wnt/β-Catenin Signaling in Human KG-1a Leukemia Cells

Background:Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs. Therefore,targeting β-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether Triterpene Glycosides(A, DA and KCY4),the active components of the traditional medicine Cimicifuga foetida, regulate β-catenin expression in leukemia cells.

Methodology and Principal Findings:Triterpene glycosides(A, DA and KCY4) from Cimicifuga foetida, which grow in black stone town in Guizhou, had been isolated and reported their molecular structure and anti-tumor activity. In this study, we injected KG-1a cells into NOD/SCID mice to establish animal model of acute myelogenous leukemia(AML), and intervened model by three kinds of triterpene glycosides(A, DA and KCY4). Observing mice living conditions, cell cycle and apoptosis rate were analyzed by flow cytometry (FCM), meanwhile, protein expression changes of β-catenin, APC and cyclinD1 were tested by immunohistochemistry (IHC). The results demonstrated the function of medium concentration of triterpene glycosides against AML KG-1a cells was induced by self-renewal of Wnt/β-catenin signaling pathways in LSCs G1 arrest and apoptosis. Apparently, mediating the induction of expression of two key factors (APC and CyclinD1) could effect expression of β-catenin. It may play an important role in induction of G1 arrest and apoptosis by the self-renewal of Wnt/β-catenin signaling pathways.

Significance: Our findings show for the first time that Triterpene glycosides(A, DA and KCY4) from Cimicifuga foetida selectively reduces β-catenin stability in AML KG-1a cells. This suppressive effect is mediated by regulating APC and CyclinD1. The effect of KCY4 is more powerful than that of A or DA.KCY4 is likely to be used as a novel strategy to eradicate leukemia via elimination of LSCs.