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Pharmaceuticals 2019, 12(1), 33; https://doi.org/10.3390/ph12010033

Characterisation of an Isogenic Model of Cisplatin Resistance in Oesophageal Adenocarcinoma Cells

1
Department of Surgery, Trinity Translational Medicine Institute, St. James’s Hospital, Trinity College Dublin, Dublin 8, Ireland
2
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK
3
UCD Conway Institute & UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 19 December 2018 / Revised: 14 February 2019 / Accepted: 15 February 2019 / Published: 20 February 2019
(This article belongs to the Special Issue Anticancer Drugs)
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Abstract

Cisplatin (cis-diamminedichloroplatinum) is widely used for the treatment of solid malignancies; however, the development of chemoresistance hinders the success of this chemotherapeutic in the clinic. This study provides novel insights into the molecular and phenotypic changes in an isogenic oesophageal adenocarcinoma (OAC) model of acquired cisplatin resistance. Key differences that could be targeted to overcome cisplatin resistance are highlighted. We characterise the differences in treatment sensitivity, gene expression, inflammatory protein secretions, and metabolic rate in an isogenic cell culture model of acquired cisplatin resistance in OAC. Cisplatin-resistant cells (OE33 Cis R) were significantly more sensitive to other cytotoxic modalities, such as 2 Gy radiation (p = 0.0055) and 5-fluorouracil (5-FU) (p = 0.0032) treatment than parental cisplatin-sensitive cells (OE33 Cis P). Gene expression profiling identified differences at the gene level between cisplatin-sensitive and cisplatin-resistant cells, uncovering 692 genes that were significantly altered between OE33 Cis R cells and OE33 Cis P cells. OAC is an inflammatory-driven cancer, and inflammatory secretome profiling identified 18 proteins secreted at significantly altered levels in OE33 Cis R cells compared to OE33 Cis P cells. IL-7 was the only cytokine to be secreted at a significantly higher levels from OE33 Cis R cells compared to OE33 Cis P cells. Additionally, we profiled the metabolic phenotype of OE33 Cis P and OE33 Cis R cells under normoxic and hypoxic conditions. The oxygen consumption rate, as a measure of oxidative phosphorylation, is significantly higher in OE33 Cis R cells under normoxic conditions. In contrast, under hypoxic conditions of 0.5% O2, the oxygen consumption rate is significantly lower in OE33 Cis R cells than OE33 Cis P cells. This study provides novel insights into the molecular and phenotypic changes in an isogenic OAC model of acquired cisplatin resistance, and highlights therapeutic targets to overcome cisplatin resistance in OAC. View Full-Text
Keywords: oesophageal cancer; treatment resistance; cisplatin; metabolism; inflammation; radiation oesophageal cancer; treatment resistance; cisplatin; metabolism; inflammation; radiation
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Buckley, A.M.; Bibby, B.A.; Dunne, M.R.; Kennedy, S.A.; Davern, M.B.; Kennedy, B.N.; Maher, S.G.; O’Sullivan, J. Characterisation of an Isogenic Model of Cisplatin Resistance in Oesophageal Adenocarcinoma Cells. Pharmaceuticals 2019, 12, 33.

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