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Open AccessArticle

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

1
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, via L. De Crecchio 7, 80138 Naples, Italy
2
Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Contrada Camporeale, 83031 Ariano Irpino (AV), Italy
3
Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, via L. De Crecchio 7, 80138 Naples, Italy
4
Consorzio Sannio Tech-AMP Biotec, Appia Str. 7, BN 82030 Apollosa, Italy
5
Institute of Food Sciences, National Research Council, Roma Str. 64, 83100 Avellino, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(15), 3836; https://doi.org/10.3390/ijms20153836
Received: 12 July 2019 / Revised: 1 August 2019 / Accepted: 2 August 2019 / Published: 6 August 2019
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. View Full-Text
Keywords: anticancer drug; apoptosis; autophagy; ER stress; natural compound; reactive oxygen species (ROS) anticancer drug; apoptosis; autophagy; ER stress; natural compound; reactive oxygen species (ROS)
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MDPI and ACS Style

Zappavigna, S.; Cossu, A.M.; Abate, M.; Misso, G.; Lombardi, A.; Caraglia, M.; Filosa, R. A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma. Int. J. Mol. Sci. 2019, 20, 3836.

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