N-bromotaurine surrogates for loss of antiproliferative response and enhances cisplatin efficacy in cancer cells with impaired glucocorticoid receptor



Logotheti, Stella, Khoury, Nikolas, Vlahopoulos, Spiros A, Skourti, Elena, Papaevangeliou, Dimitra, Liloglou, Triantafyllos ORCID: 0000-0003-0460-1404, Gorgoulis, Vassilis, Budunova, Irina, Kyriakopoulos, Anthony M and Zoumpourlis, Vassilis
(2016) N-bromotaurine surrogates for loss of antiproliferative response and enhances cisplatin efficacy in cancer cells with impaired glucocorticoid receptor. TRANSLATIONAL RESEARCH, 173 (Mol En). pp. 58-73.

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Abstract

Glucocorticoids (GCs) are frequently used in anticancer combination regimens; however, their continuous use adds selective pressure on cancer cells to develop GC-resistance via impairment of the glucocorticoid receptor (GR), therefore creating a need for GC-alternatives. Based on the drug repurposing approach and the commonalities between inflammation and neoplasia, drugs that are either in late-stage clinical trials and/or already marketed for GC-refractory inflammatory diseases could be evaluated as GC-substitutes in the context of cancer. Advantageously, unlike new molecular entities currently being de novo developed to restore GC-responsiveness of cancer cells, such drugs have documented safety and efficacy profile, which overall simplifies their introduction in clinical cancer trials. In this study, we estimated the potential of a well-established, multistage, cell line-based, mouse skin carcinogenesis model to be exploited as an initial screening tool for unveiling covert GC-substitutes. First, we categorized the cell lines of this model to GC-sensitive and GC-resistant, in correlation with their corresponding GR status, localization, and functionality. We found that GC-resistance starts in papilloma stages, due to a dysfunctional GR, which is overexpressed, DNA binding-competent, but transactivation-incompetent in papilloma, squamous, and spindle stages of the model. Then, aided by this tool, we evaluated the ability of N-bromotaurine, a naturally occurring, small-molecule, nonsteroid anti-inflammatory drug which is under consideration for use interchangeably/in replacement to GCs in skin inflammations, to restore antiproliferative response of GC-resistant cancer cells. Unlike GCs, N-bromotaurine inhibited cell-cycle progression in GC-resistant cancer cells and efficiently synergized with cisplatin, thus indicating a potential to be exploited instead of GCs against cancer.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Animals, Humans, Mice, Skin Neoplasms, Disease Models, Animal, Disease Progression, Cisplatin, Taurine, Receptors, Glucocorticoid, DNA, Glucocorticoids, Cell Cycle, Cell Proliferation, Response Elements, Protein Binding, Protein Transport, Drug Resistance, Neoplasm, Transcriptional Activation, Carcinogenesis
Depositing User: Symplectic Admin
Date Deposited: 10 Feb 2017 09:59
Last Modified: 16 Mar 2024 08:13
DOI: 10.1016/j.trsl.2016.03.009
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3005705