Saintas, Emily and Abrahams, Liam and Ahmed, Gulshan T and Ajakaiye, Anu-Oluwa M and AlHumaidi, Abdulaziz S H A M and Ashmore-Harris, Candice and Clark, Iain and Dura, Usha K and Fixmer, Carine N and Ike-Morris, Chinedu and Mato Prado, Mireia and Mccullough, Danielle and Mishra, Shishir and Schoeler, Katia M U and Timur, Husne and Williamson, Maxwell D C and Alatsatianos, Markella and Bahsoun, Basma and Blackburn, Edith and Hogwood, Catherine E.M. and Lithgow, Pamela E and Rowe, Michelle L. and Yiangou, Lyto and Rothweiler, Florian and Cinatl jr, Jindric and Zehner, Richard and Baines, Anthony J. and Garrett, Michelle D. and Gourlay, Campbell W. and Griffin, Darren K. and Gullick, William J. and Hargreaves, Emma and Howard, Mark J. and Lloyd, Daniel R. and Rossman, Jeremy S. and Smales, Christopher Mark and Tsaousis, Anastasios D. and von der Haar, Tobias and Wass, Mark N. and Michaelis, Martin (2017) 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. PLoS ONE, 12 (2). e0172140.
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.
RM Therapeutics. Pharmacology
University of Kent