Abstract
Eupafolin, a flavone found in Artemisia princeps, has been reported for its anti-tumor activity in several cancer cells. In this study, we examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that eupafolin alone and TRAIL alone had no effect on apoptosis. However, combined treatment with eupafolin and TRAIL markedly induced apoptosis in human renal carcinoma (Caki) cells, glioma cells (U251MG), and prostate cancer cells (DU145), but not normal cells [mesangial cells (MC) and normal mouse kidney cells (TCMK-1)]. Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in cathepsin S-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. In addition, eupafolin increased Bim expression at the post-translational levels via AMP-activated protein kinase (AMPK)-mediated inhibition of proteasome activity. Knock-down of Bim expression by siRNA inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells.
Highlights
Eupafolin (6-methoxy 5, 7, 30, 40-tetrahydroxyflavone) is a flavone extracted from the Artemisia princeps
Because eupafolin has anti-tumor activity in several cancer cells [3, 4], we investigated whether eupafolin could sensitize Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human renal carcinoma Caki cells
Eupafolin markedly reduced membrane potential (MMP) levels, and increased cytosolic cytochrome c release in combined treatment with eupafolin and TRAIL (Figure 1K). These results suggest that combined treatment with eupafolin and TRAIL can induce caspase-dependent apoptosis in Caki cells
Summary
Eupafolin (6-methoxy 5, 7, 30, 40-tetrahydroxyflavone) is a flavone extracted from the Artemisia princeps. It has been widely used by Chinese or native Indians as traditional medicine [1]. It has been reported that eupafolin induces apoptosis in human cervical adenocarcinoma cells through induction of mitochondrial membrane depolarization [3]. Eupafolin suppresses proliferation and growth of prostate cancer cells through inhibition of PI3K activity [4]. Molecular mechanisms underlying the anti-cancer effects of eupafolin can be associated with activation of caspase [3], downregulation of anti-apoptotic proteins [3] and the inhibition of Akt signaling pathway [4]. The exact mechanism of anti-cancer effect of eupafolin remains elusive
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