Abstract
5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated by MTT assay. The effects of the compound on apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array, Real Time qPCR, confocal microscopy analysis and the western blotting technique. Our results showed that EA-100C Red had a higher anti-proliferative effect on LN229 as compared to U87MG cells. The compound induced a significant increase of apoptosis and autophagy and up-regulated pro-apoptotic genes (Bcl3, BNIP3L, and NFKBIA) in both GBM cell lines. In this light, we studied the effects of EA-100C red on the expression of CHOP and XBP1, that are implicated in ER-stress-mediated cell death. In summary, our findings revealed that EA-100C red induced ER stress-mediated apoptosis associated to autophagy in GBM cells through CHOP and Beclin1 up-regulation and activation of caspases 3, 9, JNK and NF-kappaB pathway. On these bases, EA-100C red could represent a promising compound for anti-cancer treatment.
Highlights
Glioblastoma (GBM) is one of the most frequent malignant cancers occurring in the human brain
We showed that quinone derivative RF-Id, a novel 5-LO inhibitor [16,17,18,19,20,21,22,23,24,25], was able to inhibit the inhibitor of apoptosis proteins (IAPs) and to induce cell death in GBM cells
In order to study the antitumor action of the novel hydroquinone-based derivative TDD named EA-100C red, we assessed the effects of the compound on the proliferation of GBM cell lines (U87MG and LN229) after 24, 48 and 72 h of treatment
Summary
Glioblastoma (GBM) is one of the most frequent malignant cancers occurring in the human brain. Our group has synthesized and characterized several agents such as quinone-based derivatives with anti-cancer and anti-inflammatory properties [12,13,14,15,16,17,18,19,20,21,22,23] These studies on the development of quinone-based compounds with antitumor activity have led to investigate the natural compound embelin and its analogues known as inhibitors of 5-LO and able to suppress proliferation of GBM cells [24]. In the light of the potent activity of this novel compound as 5-LO inhibitor, we studied the potential molecular mechanisms at the basis of its anti-tumor effects
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