Eurycomalactone Inhibits Expression of Endothelial Adhesion Molecules at a Post-Transcriptional Level.

ABSTRACT: The C-19 quassinoid eurycomalactone (1) has recently been shown to be a potent (IC50 = 0.5 ?M) NF-?B inhibitor in a luciferase reporter model. In this study, we show that 1 with similar potency inhibited the expression of the NF-?B-dependent target genes ICAM-1, VCAM-1, and E-selectin in TNF?-activated human endothelial cells (HUVECtert) by flow cytometry experiments. Surprisingly, 1 (2 ?M) did not inhibit TNF?-induced IKK?/? or I?B? phosphorylation significantly. Also, the TNF?-induced degradation of I?B? remained unchanged in response to 1 (2 ?M). In addition, pretreatment of HUVECtert with 1 (2 ?M) had no statistically significant effect on TNF?-mediated nuclear translocation of the NF-?B subunit p65 (RelA). Quantitative RT-PCR revealed that 1 (0.5-5 ?M) exhibited diverse effects on the TNF?-induced transcription of ICAM-1, VCAM-1, and SELE genes since the mRNA level either remained unchanged (ICAM-1, E-selectin, and VCAM-1 at 0.5 ?M 1), was reduced (VCAM-1 at 5 ?M 1), or even increased (E-selectin at 5 ?M 1). Finally, the time-dependent depletion of a short-lived protein (cyclin D1) as well as the measurement of de novo protein synthesis in the presence of 1 (2-5 ?M) suggested that 1 might act as a protein synthesis inhibitor rather than an inhibitor of early NF-?B signaling.

SUBMITTER: Malainer C 

PROVIDER: S-EPMC5744186 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature