title: Sorafenib treatment during partial hepatectomy reduces tumorgenesis in an inflammation-associated liver cancer model.
abstract: 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.
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Zahavi
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Lanton
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel, Israel.
authors.forename: Mali Salmon
authors.initials: MS
authors.lastname: Divon
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Salmon
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Axelrod
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D006498:Hepatectomy; D006505:Hepatitis / Q000150:complications; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000150:complications*; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D009536:Niacinamide; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D000077157:Sorafenib; D000097202:ATP-Binding Cassette Sub-Family B Member 4
keywords: Mdr2 knockout; Sorafenib; hepatectomy; liver cancer; stellate cells