Tumoral response and tumoral phenotypic changes in a rat model of diethylnitrosamine-induced hepatocellular carcinoma after salirasib and sorafenib administration.

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State: Public
Version: Final published version
Serval ID
serval:BIB_CAEB3B704903
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Tumoral response and tumoral phenotypic changes in a rat model of diethylnitrosamine-induced hepatocellular carcinoma after salirasib and sorafenib administration.
Journal
OncoTargets and therapy
Author(s)
Ciccarelli O., Colson A., De Saeger C., Reding R., Sempoux C., Leclercq I.A., Stärkel P.
ISSN
1178-6930 (Print)
ISSN-L
1178-6930
Publication state
Published
Issued date
2018
Peer-reviewed
Oui
Volume
11
Pages
7143-7153
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Several intracellular signaling pathways that are deregulated during hepatocarcinogenesis might constitute potential targets for hepatocellular carcinoma (HCC) therapy. The aim of this study was to test the potential synergic antitumor effect of salirasib and sorafenib in a diethylnitrosamine (DEN)-induced HCC model in rat. The hypothesis of tumor phenotype changes during treatment was also analyzed.
DEN was administered to Wistar rats during 9 weeks to induce cirrhosis and liver cancer. After tumor development, rats were treated with intraperitoneal injections of dimethyl sulfoxide (DMSO), or salirasib, and/or with oral sorafenib 5 days/week, during 4 weeks. At sacrifice, number and size of liver tumors as well as tumor burden were recorded, and all liver tumors were processed for histological and immunohistological analyses.
Mortality rate was significantly higher in rats treated with salirasib and/or sorafenib than in the control group ( <i>P</i> =0.001). Tumor burden was smaller in the treated group compared with the DMSO control group ( <i>P</i> =0.044), but a synergistic effect of the two chemotherapies could not be observed. In 62.5% of rats (10/16) treated with salirasib and/or sorafenib, a cytokeratin-7 and -19-positive hepatocholangiocellular carcinoma (HCC/CHC) was found vs 20% (5/25) developing such phenotype in the DMSO control group ( <i>P</i> =0.018). Ki67 immunostaining showed significantly reduced tumor cell proliferation in treated rats ( <i>P</i> =0.001), whereas apoptosis as assessed by caspase-3 activity in cell lysate was similar in all groups.
The addition of sorafenib to salirasib did not seem to provide any synergistic therapeutic effect in this study. Both chemotherapeutic agents, administered alone or in combination, induced tumoral phenotypic changes in the majority of rats, a finding not associated with an increased tumor cell proliferation or decreased apoptosis. The rat model described in this work constitutes the first experimental tool generating putatively more aggressive combined HCC/CHC tumors following chemotherapy. Further work is required to better characterize this clinically relevant phenomenon.
Keywords
Pharmacology (medical), Oncology, chemotherapy, disease management, liver neoplasms, liver transplantation
Pubmed
Web of science
Open Access
Yes
Create date
05/11/2018 18:20
Last modification date
20/08/2019 15:45
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