Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines

Arnould, Stéphanie; Hennebelle, Isabelle; Canal, Pierre; Bugat, R.; Guichard, Sylvie

doi:10.1016/s0959-8049(02)00411-2

Cited by 148 publications

(117 citation statements)

References 24 publications

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“…Our in vivo data confirmed the in vitro findings and showed that the combination of SCH-527123 and oxaliplatin significantly inhibits tumor growth when compared with single agents alone. ERCC1 mRNA levels have been shown to be predictive of oxaliplatin cytotoxicity in the HCT116 cell line (25) and a useful marker in predicting response to oxaliplatin-based treatment for colorectal cancer patients (44). High ERCC1 mRNA expression has been shown to be associated with resistance to oxaliplatin (26).…”

Section: Discussionmentioning

confidence: 99%

“…5D). Excision repair cross-complement group1 (ERCC1) is a key element in the nucleotide excision repair pathway which has previously been associated with oxaliplatin resistance (24)(25)(26). Therefore, the effect of treatment on ERCC1 mRNA expression in the xenografts following SCH-527123, oxaliplatin alone, and their combination was measured by qRT-PCR.…”

Section: Sch-527123 Alone or In Combination With Oxaliplatin Enhancedmentioning

confidence: 99%

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The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

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LaBonte

Zhang

et al. 2012

Molecular Cancer Therapeutics

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Colorectal cancer is the second most common cause of cancer-related death in the United States. Recent studies showed that interleukin-8 (IL-8) and its receptors (CXCR1 and CXCR2) are significantly upregulated in both the tumor and its microenvironment, and act as key regulators of proliferation, angiogenesis, and metastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines. Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-kB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed that the combination of SCH-527123 and oxaliplatin resulted in a greater decrease in cell proliferation, tumor growth, apoptosis, and angiogenesis that was superior to single-agent treatment. Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis. In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Sch-527123 Alone or In Combination With Oxaliplatin Enhancedmentioning

confidence: 99%

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

Ning

LaBonte

Zhang

et al. 2012

Molecular Cancer Therapeutics

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“…However, the most important mechanisms seem to be related to dna repair: mmr, or nucleotide excision repair (ner). Cells that overexpress ercc1, an excision repair enzyme, are resistant to oxaliplatin 15 .…”

Section: Resistance To Oxaliplatinmentioning

confidence: 99%

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

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“…Because ERCC1 catalyses the 5 0 incision at the damage site (Reed, 1998), its expression and functionality are crucial for NER activity. Moreover, its overexpression has been reported to be correlated with oxaliplatin resistance (Arnould et al, 2003). Thus, we investigated whether the NER could be targeted by the combined treatment of oxaliplatin plus cetuximab through the regulation of ERCC1 and XPA expression at the translational and transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation

Balin-Gauthier

Delord

et al. 2008

Br J Cancer

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Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferasemediated oxaliplatin detoxification, DNA -platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin -DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin -DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation.

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Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines

Cited by 148 publications

References 24 publications

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation

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