Abstract
BackgroundEmbelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms.MethodsU87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique.ResultsHere, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway.Conclusions RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0440-x) contains supplementary material, which is available to authorized users.
Highlights
Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting X-linked inhibitor of apoptosis protein (XIAP) and NF-κB signaling pathway
Effects of RF-Id on the proliferation of GBM cells In order to investigate the antitumor activity of the new benzoquinone derivatives, we evaluated the effects of RFId, RF-Idmet and embelin on cell growth of two human
RF-Id inhibits XIAP-cIAP2 interaction Since RF-Id dowregulated genes belonged to IAP family and NFκB pathway and embelin inhibits the X-linked inhibitor of apoptosis protein (XIAP) by binding to its Baculovirus Inhibitor of apoptosis protein Repeat (BIR) domain, we investigated the action mechanism of the compound
Summary
Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms. The blood–brain barrier (BBB) is the most important limiting factor for the development of new drugs and drug delivery for the central nervous system (CNS) [5]. In this context, we showed that the newly developed transferrin (Tf)-targeted self-assembling nanoparticles (NPs) incorporating zoledronic acid (ZOL) allowed the successfully use of ZOL in the treatment of GBM, potentiating its in vitro and in vivo antitumor activity on GBM through the acquisition of ability to cross the BBB [6]. Further progress towards a cure for malignant gliomas will require a greater understanding of the underlying mechanisms driving the growth and resistance to therapy of these tumors
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