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.

Genome-wide single-nucleotide resolution of oxaliplatin–DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines

“…Enhanced excision repair capacity has been proposed as a contributing factor in cellular resistance to platinating anticancer drugs; however the current data to support this notion are inconsistent and fail to address confounding factors (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). To our knowledge, ours is the most comprehensive study to address this issue, compounding multiple novel methods to create the most complete characterization of nucleotide excision repair in cancer cell lines.…”

“…However many of the results are not reproducible and are often confounded by the multiple roles of individual proteins. Thus the link between alterations in nucleotide excision repair and response to platinum based chemotherapies remains unclear (19,20). In this study, we use novel methods to provide a comprehensive profile of repair efficiency for a panel of colorectal cancer cell lines that vary in oxaliplatin sensitivity by an order of magnitude.…”

Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

“…In conclusion, we demonstrated here that Mps1 depletion or inhibition kills high-risk neuroblastoma cells in vitro and in vivo. Our study proposes new windows in the context of cancer therapy given that these paediatric tumours display high resistance to conventional anticancer regimens such as DNA damaging agents 59,60 .…”

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma

“…Cisplatin (CDDP) is applied as a frontline chemotherapy agent for neuroblastoma patients, including the high-risk cases [ 11 ]. Like other platinum-based chemotherapeutic agents, CDPP’s efficacy relies on DNA damaging effects, which often fails due to the innate and acquired resistance prevalent among tumor cells [ 12 ]. Cell line models of neuroblastoma exhibit heterogeneity in their CDDP response due to the resistance mechanisms underlying their drug sensitivity.…”