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Impact of the APE1 Redox Function Inhibitor E3330 in Non-Small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal
2
Research Center for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
3
Lung Cancer Unit, Champalimaud Centre for the Unknown, Av. Brasília, 1400-038 Lisboa, Portugal
4
Laboratory of Cellular and Molecular Biology, Institute for Health Science Research Germans Trias i Pujol (IGTP), Campus Can Ruti, Ctra de Can Ruti, Camí de les Escoles, s/n, 08916 Badalona, Barcelona, Spain
5
Internal Medicine Department, Universitat Autónoma de Barcelona, Campus de la UAB, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(6), 550; https://doi.org/10.3390/antiox9060550
Received: 12 May 2020 / Revised: 8 June 2020 / Accepted: 22 June 2020 / Published: 24 June 2020
(This article belongs to the Special Issue Redox-Active Molecules as Therapeutic Agents)
Elevated expression levels of the apurinic/apyrimidinic endonuclease 1 (APE1) have been correlated with the more aggressive phenotypes and poor prognosis of non-small cell lung cancer (NSCLC). This study aimed to assess the impact of the inhibition of the redox function of APE1 with E3330 either alone or in combination with cisplatin in NSCLC cells. For this purpose, complementary endpoints focusing on cell viability, apoptosis, cell cycle distribution, and migration/invasion were studied. Cisplatin decreased the viability of H1975 cells in a time- and concentration-dependent manner, with IC50 values of 9.6 µM for crystal violet assay and 15.9 µM for 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. E3330 was clearly cytotoxic for concentrations above 30 µM. The co-incubation of E3330 and cisplatin significantly decreased cell viability compared to cisplatin alone. Regarding cell cycle distribution, cisplatin led to an increase in sub-G1, whereas the co-treatment with E3330 did not change this profile, which was then confirmed in terms of % apoptotic cells. In addition, the combination of E3330 and cisplatin at low concentrations decreased collective and chemotactic migration, and also chemoinvasion, by reducing these capabilities up to 20%. Overall, these results point to E3330 as a promising compound to boost cisplatin therapy that warrants further investigation in NSCLC. View Full-Text
Keywords: non-small cell lung cancer; cisplatin; apurinic/apyrimidinic endonuclease 1; E3330; cytotoxicity; apoptosis; migration; invasion non-small cell lung cancer; cisplatin; apurinic/apyrimidinic endonuclease 1; E3330; cytotoxicity; apoptosis; migration; invasion
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Manguinhas, R.; Fernandes, A.S.; Costa, J.G.; Saraiva, N.; Camões, S.P.; Gil, N.; Rosell, R.; Castro, M.; Miranda, J.P.; Oliveira, N.G. Impact of the APE1 Redox Function Inhibitor E3330 in Non-Small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion. Antioxidants 2020, 9, 550.

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