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

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 173; pp. 58 - 73.e2
• Main Authors: Logotheti, Stella, Khoury, Nikolas, Vlahopoulos, Spiros A, Skourti, Elena, Papaevangeliou, Dimitra, Liloglou, Triantafyllos, Gorgoulis, Vassilis, Budunova, Irina, Kyriakopoulos, Anthony M, Zoumpourlis, Vassilis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2016
• Subjects: Animals; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin - pharmacology; Disease Models, Animal; Disease Progression; DNA - metabolism; Drug Resistance, Neoplasm - drug effects; Glucocorticoids - pharmacology; Humans; Internal Medicine; Mice; Protein Binding - drug effects; Protein Transport - drug effects; Receptors, Glucocorticoid - metabolism; Response Elements - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Taurine - analogs & derivatives; Taurine - pharmacology; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; glucocorticoid; glucocorticoid receptor; N-bromotaurine; drug re-purposing; NSAID; qRT-PCR; N-chlorotaurine; fluorescence-activated cell sorting; glucocorticoid resistance; GR; FACS; glucocorticoid receptor element; electrophoretic mobility shift assay; quantitative Real-Time-Polymerase Chain Reaction; skin carcinogenesis; EMSA; BrTaur; GRE; GC; ClTaur; non-steroid anti-inflammatory drug
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2016.03.009

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, NSAID 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.