RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver

• Published in: Journal of surgical oncology Vol. 107; no. 4; pp. 393 - 401
• Main Authors: Shi, Ji-Hua, Liu, Shu-Zheng, Wierød, Lene, Scholz, Hanne, Anmarkrud, Jarl Andreas, Huitfeldt, Henrik S., Zhang, Shui-Jun, Line, Pål-Dag
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-03-2013; Wiley Subscription Services, Inc
• Subjects: Animals; Antineoplastic Agents - pharmacology; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - surgery; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Fluorescent Antibody Technique; Hepatectomy - adverse effects; Hepatectomy - methods; hepatocellular carcinoma; Hepatocytes - drug effects; Humans; Immunohistochemistry; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Liver Neoplasms - surgery; Liver Neoplasms, Experimental - drug therapy; liver regeneration; Liver Regeneration - drug effects; Molecular Targeted Therapy - methods; Neoplasm Micrometastasis; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenylurea Compounds - pharmacology; Protein Kinase Inhibitors - pharmacology; raf Kinases - antagonists & inhibitors; Rats; tumor recurrence
• ISSN: 0022-4790; 1096-9098
• DOI: 10.1002/jso.23224

Background
Post‐operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post‐operative liver regeneration.
Objective
To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model.
Methods
Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B‐RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers.
Results
Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B‐RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes.
Conclusions
The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment. J. Surg. Oncol. 2013;107:393–401. © 2012 Wiley Periodicals, Inc.