title: N-bromotaurine surrogates for loss of antiproliferative response and enhances cisplatin efficacy in cancer cells with impaired glucocorticoid receptor.
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.
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Logotheti
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Khoury
authors.affiliation: Horemio Research Institute, First Department of Pediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Spiros A
authors.initials: SA
authors.lastname: Vlahopoulos
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Elena
authors.initials: E
authors.lastname: Skourti
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Papaevangeliou
authors.affiliation: University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Liloglou
authors.affiliation: Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, Ill, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Budunova
authors.affiliation: Nasco AD, Biotechnology Laboratory, Piraeus, Greece.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Kyriakopoulos
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece. Electronic address: vzub@eie.gr.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zoumpourlis
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D013654:Taurine; C052954:N-bromotaurine; D004247:DNA; D002945:Cisplatin