Background and Aims: Currently, the most promising strategy to prolong survival of patients with the diagnosis
of primary HCC is the use of the multi kinase inhibitor Sorafenib. We now investigated
benefits of the serin/threonine kinase inhibitor 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole
(DMAT), which inhibits activity of CK2, PDK1, PIM-1 and PIM-3 at almost equimolar
IC50. We investigated hepatoma cell survival and experimental HCC growth and compared
mechanisms of DMAT and Sorafenib action. Methods: Viability and apoptosis following DMAT incubation were measured in the human hepatoma
cell lines HepG2 and Huh7 by MTT- and caspase-3-activity-assay. Experimental HCC was
induced in NMRI nude mice by subcutaneous injection of HepG2 cells. Tumor growth,
proliferation, apoptosis, biochemical and histological changes following DMAT administration
were monitored. CK2 activity in tumorous and non-tumorous liver tissue, CK2, PDK1,
PIM-1 and PIM-3 expressions in primary mouse hepatocytes and hepatoma cells, as well
as effects of DMAT and Sorafenib on NFkB activity and wnt signalling were measured.
Inhibition of individual kinases was obtained by the use of cell lines stably expressing
shRNA. Results: DMAT incubation of hepatoma cells significantly reduced proliferation, but did not
increase apoptosis. DMAT treatment of mice interfered with tumor growth and tumor
proliferation without affecting healthy liver tissue. DMAT and Sorafenib interfered
with NFkB activation and wnt signaling. Of the DMAT target kinases only CK2 and PIM-3
were found to be over-expressed in hepatoma cells. The knockdown of PIM-3 was most
efficient in reduction of hepatoma cell proliferation. Conclusions: PIM-3 and also CK2 contribute to tumor growth e.g. by triggering the wnt signalling
pathway and NFkB expression. Inhibition, either by application of inhibitors, such
as DMAT, or by specific expressional down modulation, might represent a promising
therapeutic approach in future HCC therapy.
