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.

Emily Saintas,Campbell W Gourlay,Husne Timur,Tobias Von Der Haar,Anthony J Baines,Daniel R Lloyd,Emma Hargreaves,Jeremy S Rossman,Chinedu Ike-Morris,Darren K Griffin,Markella Alatsatianos,C Mark Smales,Mireia Mato Prado,Lyto Yiangou,Candice Ashmore-Harris,Liam Abrahams,Basma Bahsoun,Mark N Wass,Michelle D Garrett,Anastasios D Tsaousis,William J Gullick,Martin Michaelis,Mark J Howard,Richard Zehner,Florian Rothweiler,E K Blackburn ,Katia M U Schöler ,Abdulaziz S H A M Alhumaidi ,Carine N Fixmer ,S K Mishra ,Jindřich Činátl ,Iain C Clark ,Anu-Oluwa M Ajakaiye ,Michelle L Rowe ,Catherine E.m Hogwood ,Danielle J Mccullough ,Maxwell D C Williamson ,Gulshan T Ahmad ,Pamela E Lithgow ,Usha K Dura

doi:10.1371/journal.pone.0172140

Emily Saintas, Campbell W Gourlay + Show 38 more

Open Access

https://doi.org/10.1371/journal.pone.0172140

Copy DOI

Journal: PloS one	Publication Date: Feb 13, 2017
Citations: 7	License type: CC BY 4.0

Affiliation: University of Kent, Goethe University Frankfurt

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.

Highlights

Despite continuous progress over past decades, the prognosis for cancer patients whose disease cannot be controlled locally remains generally unsatisfactory
The oxaliplatin-resistant SK-N-AS sub-line SK-N-ASrOXALI4000 adapted to growth in the presence of oxaliplatin 4000 ng/mL was derived from the resistant cancer cell line (RCCL) collection and had been established by previously described methods [22]
Prior to the start of the project, the identity of SK-N-AS and SK-N-ASrOXALI4000 was confirmed by short tandem repeat (STR) analysis (S1 Table)

Summary

Introduction

Despite continuous progress over past decades, the prognosis for cancer patients whose disease cannot be controlled locally remains generally unsatisfactory. Effective systemic therapies are needed to improve treatment outcome. A major obstacle in the development of such therapies is the occurrence of drug resistance. Cancer cell drug resistance can be intrinsic, i.e. there is no initial therapy response in previously untreated patients, or acquired, i.e. tumours initially respond to therapy but eventually become resistant resulting in treatment failure [3]. An improved understanding of the processes underlying resistance acquisition is needed to develop improved therapies. Drug-adapted cancer cell lines are preclinical model systems that are used to study resistance formation in cancer cells and that have been shown to reflect clinical mechanisms of acquired resistance [4,5,6,7,8,9]

Methods

Results

Conclusion