Sorafenib treatment during partial hepatectomy reduces tumorgenesis in an inflammation-associated liver cancer model
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Tamar Zahavi1,*, Tali Lanton2,*, Mali Salmon Divon3,*, Asher Salmon1, Tamar Peretz1, Eithan Galun2, Jonathan H. Axelrod2, Amir Sonnenblick1
1Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3Department of Molecular Biology, Ariel University, Ariel, Israel
*These authors have contributed equally to this work
Amir Sonnenblick, e-mail: firstname.lastname@example.org
Keywords: Sorafenib, hepatectomy, liver cancer, stellate cells, Mdr2 knockout
Received: November 05, 2015 Accepted: November 24, 2015 Published: December 17, 2015
The long-term prognosis after resection of hepatocellular carcinoma (HCC), which is one of the treatment options for early-stage HCC, remains unsatisfactory as a result of a high incidence of disease recurrence. Recent studies performed in murine models revealed a link between liver regeneration under chronic inflammation and hepatic tumorigenesis. Sorafenib is a potent drug for advanced HCC with multikinase inhibition activity. We propose that inhibition of signal transduction pathways which are activated during hepatectomy, using Sorafenib, will reduce accelerated tumorigenesis. To test this hypothesis, we studied the Mdr2-knockout (KO) mouse strain, a model of inflammation-associated cancer, which underwent partial hepatectomy (PHx) at three months of age, with or without Sorafenib.
Here we show that Sorafenib treatment during PHx inhibited different signal transduction pathways at the multikinase levels, but did not result in increased morbidity or mortality. At the early stages after PHx, Sorafenib treatment had no effect on the course of proliferation, apoptosis and DNA repair in the regenerating liver, but resulted in decreased stellate cells activation and inflammatory response. Finally, we show that Sorafenib treatment during PHx at three months of age resulted in decreased fibrosis and tumor formation at 8.5 months.
In conclusion our study indicates that short-term Sorafenib treatment during PHx is safe and effective in inhibiting inflammation-associated cancer, and is therefore a potential strategy for recurrence prevention in patients with early-stage HCC treated with PHx.
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