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

Paul Noordhuis,Godefridus J Peters,Richard J Honeywell,Adrianus C Laan,Kasper Van De Born

doi:10.3390/ijms20153619

Abstract

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.

Highlights

Oxaliplatin is a third generation analogue of cisplatin and has shown remarkable clinical activity in colon cancer with intrinsic resistance to cisplatin
Oxaliplatin resistance is a major clinical hurdle for curative chemotherapy since it is a crucial component of combination regimens for colorectal cancer
Much knowledge has been gained regarding mechanisms underlying resistance to the first-generation platinum compound, cisplatin, those relating to oxaliplatin resistance are still not well characterized

Summary

Introduction

Oxaliplatin is a third generation analogue of cisplatin and has shown remarkable clinical activity in colon cancer with intrinsic resistance to cisplatin. Platinum-DNA adducts mediate the pharmacological activity of oxaliplatin, leading to growth arrest and subsequent apoptosis [3,4,5]. Oxaliplatin resistance is achieved via several modalities including reduced drug uptake and/or enhanced efflux of the drug, intracellular sequestration, decreased DNA adduct formation, increased DNA repair, or increased adduct tolerance and reduced response to the platinum DNA adducts [6,7,8,9]. Differences in platinum DNA adducts and downstream signaling possibly explain the activity in colon cancers that are intrinsically resistant to cisplatin [5,15,16]. The nucleotide excision repair system (NER) involved in repair of oxaliplatin-DNA adducts has been shown to have a predictive value for the treatment of colorectal cancer [9,20,21]. Targeted inactivation of p53 in HCT116 cells decreased the activity of oxaliplatin, it was not possible to predict sensitivity based on p53 status in a group of 30 colorectal cancer cell lines [27]

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Conclusion