Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT.
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Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT. / Sass, Gabriele; Klinger, Nina; Sirma, Hüseyin; Hashemolhosseini, Said; Hellerbrand, Claus; Neureiter, Daniel; Wege, Henning; Ocker, Matthias; Tiegs, Gisa.
In: INT J ONCOL, Vol. 39, No. 2, 2, 2011, p. 433-442.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT.
AU - Sass, Gabriele
AU - Klinger, Nina
AU - Sirma, Hüseyin
AU - Hashemolhosseini, Said
AU - Hellerbrand, Claus
AU - Neureiter, Daniel
AU - Wege, Henning
AU - Ocker, Matthias
AU - Tiegs, Gisa
PY - 2011
Y1 - 2011
N2 - 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 NF?B 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 NF?B- 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.
AB - 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 NF?B 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 NF?B- 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.
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Cell Line, Tumor
KW - Gene Knockdown Techniques
KW - Cell Proliferation/drug effects
KW - Xenograft Model Antitumor Assays
KW - Cell Survival/drug effects
KW - Signal Transduction/drug effects
KW - Antineoplastic Agents/pharmacology
KW - Benzenesulfonates/pharmacology
KW - Benzimidazoles/pharmacology
KW - Carcinoma, Hepatocellular/enzymology/metabolism/pathology
KW - Casein Kinase II/genetics/metabolism
KW - Enzyme Activation/drug effects
KW - Hep G2 Cells
KW - Liver Neoplasms/enzymology/metabolism/pathology
KW - Protein Kinase Inhibitors/pharmacology
KW - Protein-Serine-Threonine Kinases/genetics/metabolism
KW - Proto-Oncogene Proteins/genetics/metabolism
KW - Pyridines/pharmacology
KW - Wnt Proteins/metabolism
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Cell Line, Tumor
KW - Gene Knockdown Techniques
KW - Cell Proliferation/drug effects
KW - Xenograft Model Antitumor Assays
KW - Cell Survival/drug effects
KW - Signal Transduction/drug effects
KW - Antineoplastic Agents/pharmacology
KW - Benzenesulfonates/pharmacology
KW - Benzimidazoles/pharmacology
KW - Carcinoma, Hepatocellular/enzymology/metabolism/pathology
KW - Casein Kinase II/genetics/metabolism
KW - Enzyme Activation/drug effects
KW - Hep G2 Cells
KW - Liver Neoplasms/enzymology/metabolism/pathology
KW - Protein Kinase Inhibitors/pharmacology
KW - Protein-Serine-Threonine Kinases/genetics/metabolism
KW - Proto-Oncogene Proteins/genetics/metabolism
KW - Pyridines/pharmacology
KW - Wnt Proteins/metabolism
M3 - SCORING: Journal article
VL - 39
SP - 433
EP - 442
JO - INT J ONCOL
JF - INT J ONCOL
SN - 1019-6439
IS - 2
M1 - 2
ER -
