Abstract
The multi-kinase-inhibitor Sorafenib has been shown to prolong survival of patients suffering from hepatocellular carcinoma (HCC). We investigated effects of the serine/threonine kinase inhibitor 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) on experimental HCC growth, and identified mechanisms and target kinases of DMAT. Our results show that DMAT application in vivo reduced tumor growth in a xenotransplant model by interference with tumor cell proliferation. Biochemical parameters and histology following DMAT administration revealed no alterations in liver tissue. Similar to Sorafenib, DMAT interfered with NFκB activation and Wnt-signaling. Of the kinases inhibited by DMAT at almost equimolar IC50, CK2 and PIM-3 were found to be over-expressed or more active in hepatoma cells and human HCC tissue. Knockdown of PIM-3 or CK2 by shRNA revealed that both kinases are important for hepatoma cell proliferation and survival. In conclusion, DMAT reduces HCC growth by interference with NFκB- and Wnt-signaling. PIM-3 and CK2 seem to be important target kinases. Inhibition of these kinases by application of inhibitors, e.g., DMAT, might represent a promising therapeutic approach in future HCC therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Benzenesulfonates / pharmacology
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Benzimidazoles / pharmacology*
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Carcinoma, Hepatocellular / enzymology
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Casein Kinase II / genetics
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Casein Kinase II / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Enzyme Activation / drug effects
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Gene Knockdown Techniques
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Hep G2 Cells
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Humans
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Liver Neoplasms / enzymology
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Male
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Mice
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NF-kappaB-Inducing Kinase
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Niacinamide / analogs & derivatives
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Phenylurea Compounds
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pyridines / pharmacology
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Signal Transduction / drug effects
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Sorafenib
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Wnt Proteins / metabolism
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Xenograft Model Antitumor Assays
Substances
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2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole
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Antineoplastic Agents
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Benzenesulfonates
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Benzimidazoles
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyridines
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Wnt Proteins
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Niacinamide
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Sorafenib
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Casein Kinase II
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PIM3 protein, human
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Protein Serine-Threonine Kinases