Abstract
We have previously reported that seventy percent ethanol extract of Chrysanthemum indicum Linne (CIE) strongly reduces Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line (LCL) survival by inhibiting virus-encoded latent infection membrane protein 1 (LMP1)-induced NF-κB activation. To identify an active compound(s) in CIE that inhibits LMP1-induced NF-κB activation, activity-guided fractionation was employed. The CH2Cl2 fraction of CIE strongly reduced LMP1-induced NF-κB activation and LCL viability with relatively low cytotoxic effects on primary human foreskin fibroblast (HFF), HeLa or Burkitt’s lymphoma (BL41) cells. Furthermore, lupeol, a pentacyclic triterpene, was identified in the CH2Cl2 fraction of CIE to attenuate LMP1-induced NF-κB activation and LCL viability. This study demonstrates that lupeol is one of active compounds in the CH2Cl2 fraction of CIE that inhibits LMP1-induced NF-κB activation and reduces NF-κB-dependent LCL viability.
Highlights
The NF-κB family of transcription factors plays an important role in tumoirgenesis, and aberrant NF-κB activation is a hallmark of many epithelial and lymphoid-derived cancers [1,2]
We have previously reported that Chrysanthemum indicum Linne extract (CIE) inhibits latent infection membrane protein 1 (LMP1)-induced NF-κB activation and lymphoblastoid cell line (LCL) viability without exhibiting any adverse effect on the viability of cells whose survival is independent of NF-κB activation [19]
The effect of the CH2Cl2 fraction of CIE on LMP1 CTAR1- or CTAR2-induced NF-κB activation was further determined by using LMP1 mutants deleted for CTAR2 or CTAR1 (Δ187-351) (Figure 2B)
Summary
The NF-κB family of transcription factors plays an important role in tumoirgenesis, and aberrant NF-κB activation is a hallmark of many epithelial and lymphoid-derived cancers [1,2]. The non-canonical NF-κB pathway which is utilized by lymphotoxin β (LT- β), B cell-activating factor of the TNF family (BAFF) and CD40 involves NF-κB inducing kinase (NIK)- and IKKαmediated proteolytic processing of p100 into p52 and nuclear translocation of the RelB/p52 complexes [5,6]. LMP1 constitutively activate both the non-canonical and the canonical NF-κB pathways through two C-terminal cytoplasmic domains referred to as C-terminal Activation Regions 1 and 2 (CTAR1 and 2), respectively, and LMP1-induced NF-κB activation is critical for EBV-transformed LCL survival [9,10,11,12,13,14,15,16,17,18]. In this study, we have expanded our investigation to identify an active compound(s) in CIE that inhibits LMP1-induced NF-κB activation and LCL viability by using activity-guided fractionation
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