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The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells
- Source :
- Journal of Experimental & Clinical Cancer Research : CR, Journal of Experimental & Clinical Cancer Research, Vol 35, Iss 1, Pp 1-14 (2016)
- Publication Year :
- 2016
-
Abstract
- Background 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. 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. Methods U87MG 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. Results Here, 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 material The online version of this article (doi:10.1186/s13046-016-0440-x) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Cancer Research
Cell Survival
Down-Regulation
Apoptosis
lcsh:RC254-282
Inhibitor of Apoptosis Proteins
Linoleic Acid
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Cell Line, Tumor
Autophagy
Benzoquinones
Humans
RF-Id
Viability assay
Enzyme Inhibitors
Caspase
Cell Proliferation
Arachidonate 5-Lipoxygenase
Arachidonic Acid
biology
Brain Neoplasms
Cell growth
Research
Apoptosi
IAP
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
XIAP
Gene Expression Regulation, Neoplastic
IAPs
Oxidative Stress
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer cell
Arachidonate 5-lipoxygenase
biology.protein
Cancer research
Drug Screening Assays, Antitumor
Glioblastoma
Signal Transduction
NFκB
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental & Clinical Cancer Research : CR, Journal of Experimental & Clinical Cancer Research, Vol 35, Iss 1, Pp 1-14 (2016)
- Accession number :
- edsair.doi.dedup.....ac13f176d37cd59d180171fb1bd3e2bd