TY - JOUR
T1 - Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
AU - Noordhuis, Paul
AU - Laan, Adrianus C.
AU - van de Born, Kasper
AU - Honeywell, Richard J.
AU - Peters, Godefridus J.
PY - 2019
Y1 - 2019
N2 - Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, gene expression arrays, and array-CGH profiling. Pulse (4 h, 4OHP) and continuous exposure (72 h, cOHP) resulted in 4.0 to 7.9-fold and 5.0 to 11.8-fold drug resistance, respectively. Cellular oxaliplatin accumulation and DNA-adduct formation were decreased and related to OCT1-3 and ATP7A expression. Gene expression profiling and pathway analysis showed significantly altered p53 signaling, xenobiotic metabolism, role of BRCA1 in DNA damage response, and aryl hydrocarbon receptor signaling pathways, were related to decreased ALDH1L2, Bax, and BBC3 (PUMA) and increased aldo-keto reductases C1 and C3. The array-CGH profiles showed focal aberrations. In conclusion, OHP resistance was correlated with total platinum accumulation and OCT1-3 expression, decreased proapoptotic, and increased anti-apoptosis and homologous repair genes.
AB - Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, gene expression arrays, and array-CGH profiling. Pulse (4 h, 4OHP) and continuous exposure (72 h, cOHP) resulted in 4.0 to 7.9-fold and 5.0 to 11.8-fold drug resistance, respectively. Cellular oxaliplatin accumulation and DNA-adduct formation were decreased and related to OCT1-3 and ATP7A expression. Gene expression profiling and pathway analysis showed significantly altered p53 signaling, xenobiotic metabolism, role of BRCA1 in DNA damage response, and aryl hydrocarbon receptor signaling pathways, were related to decreased ALDH1L2, Bax, and BBC3 (PUMA) and increased aldo-keto reductases C1 and C3. The array-CGH profiles showed focal aberrations. In conclusion, OHP resistance was correlated with total platinum accumulation and OCT1-3 expression, decreased proapoptotic, and increased anti-apoptosis and homologous repair genes.
KW - Array comparative genomic hybridization
KW - Gene expression
KW - Oxaliplatin resistance
KW - Platinum DNA adducts
KW - Platinum accumulation
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85070589236&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31344863
U2 - https://doi.org/10.3390/ijms20153619
DO - https://doi.org/10.3390/ijms20153619
M3 - Article
C2 - 31344863
SN - 1422-0067
VL - 20
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 15
ER -