Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines

Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines

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 expressio...

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Main Authors: Paul Noordhuis, Adrianus C. Laan, Kasper van de Born, Richard J. Honeywell, Godefridus J. Peters
Format: Article
Language:English
Published: MDPI AG 2019-07-01
Series:International Journal of Molecular Sciences
Subjects:
oxaliplatin resistance
platinum accumulation
platinum DNA adducts
gene expression
array comparative genomic hybridization
Online Access:https://www.mdpi.com/1422-0067/20/15/3619
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spelling doaj-fcc2a9bce53845c6a4421c0c3a7741fe2020-11-25T00:40:40ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-07-012015361910.3390/ijms20153619ijms20153619Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell LinesPaul Noordhuis0Adrianus C. Laan1Kasper van de Born2Richard J. Honeywell3Godefridus J. Peters4Department of <sup>1</sup>Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsDepartment of <sup>1</sup>Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsDepartment of <sup>1</sup>Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsDepartment of <sup>1</sup>Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsDepartment of <sup>1</sup>Medical Oncology, Amsterdam UMC, Location VU University Medical Center (VUmc), CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsOxaliplatin (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.https://www.mdpi.com/1422-0067/20/15/3619oxaliplatin resistanceplatinum accumulationplatinum DNA adductsgene expressionarray comparative genomic hybridization
collection DOAJ
language English
format Article
sources DOAJ
author Paul Noordhuis
Adrianus C. Laan
Kasper van de Born
Richard J. Honeywell
Godefridus J. Peters
spellingShingle Paul Noordhuis
Adrianus C. Laan
Kasper van de Born
Richard J. Honeywell
Godefridus J. Peters
Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
International Journal of Molecular Sciences
oxaliplatin resistance
platinum accumulation
platinum DNA adducts
gene expression
array comparative genomic hybridization
author_facet Paul Noordhuis
Adrianus C. Laan
Kasper van de Born
Richard J. Honeywell
Godefridus J. Peters
author_sort Paul Noordhuis
title Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
title_short Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
title_full Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
title_fullStr Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
title_full_unstemmed Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines
title_sort coexisting molecular determinants of acquired oxaliplatin resistance in human colorectal and ovarian cancer cell lines
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2019-07-01
description 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.
topic oxaliplatin resistance
platinum accumulation
platinum DNA adducts
gene expression
array comparative genomic hybridization
url https://www.mdpi.com/1422-0067/20/15/3619
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AT godefridusjpeters coexistingmoleculardeterminantsofacquiredoxaliplatinresistanceinhumancolorectalandovariancancercelllines
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