title: Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS.
abstract: The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
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authors.initials: CE
authors.lastname: Hogwood
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.lastname: Rowe
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
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authors.lastname: Yiangou
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Florian
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authors.lastname: Rothweiler
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
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authors.lastname: Cinatl
authors.affiliation: Institut für Rechtsmedizin, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
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authors.lastname: Zehner
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.initials: MD
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
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authors.initials: E
authors.lastname: Hargreaves
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
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authors.initials: CM
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
authors.forename: Anastasios D
authors.initials: AD
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authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.
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authors.lastname: von der Haar
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
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authors.initials: MN
authors.lastname: Wass
authors.affiliation: School of Biosciences, University of Kent, Canterbury, United Kingdom.|Industrial Biotechnology Centre, University of Kent, Canterbury, United Kingdom.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-5710-5888
authors.initials: M
authors.lastname: Michaelis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011003:Ploidies; D014466:Ultraviolet Rays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D004317:Doxorubicin; D016190:Carboplatin; D002945:Cisplatin; D000093542:Gemcitabine