Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Int J Oncol. 2011 Aug;39(2):433-42. doi: 10.3892/ijo.2011.1037. Epub 2011 May 10.
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.
多激酶抑制剂索拉非尼已被证明可延长肝细胞癌（HCC）患者的生存期。我们研究了丝氨酸/苏氨酸激酶抑制剂 2-二甲基氨基-4,5,6,7-四溴-1H-苯并咪唑（DMAT）对实验性 HCC 生长的影响，并确定了 DMAT 的作用机制和靶激酶。我们的结果表明，DMAT 在体内应用通过干扰肿瘤细胞增殖来减少异种移植模型中的肿瘤生长。DMAT 给药后的生化参数和组织学显示肝组织没有变化。与索拉非尼类似，DMAT 干扰 NFκB 激活和 Wnt 信号转导。在 DMAT 以几乎等摩尔 IC50 抑制的激酶中，CK2 和 PIM-3 在肝癌细胞和人 HCC 组织中被发现过表达或更活跃。用 shRNA 敲低 PIM-3 或 CK2 表明，这两种激酶对于肝癌细胞的增殖和存活都很重要。总之，DMAT 通过干扰 NFκB 和 Wnt 信号转导来减少 HCC 的生长。PIM-3 和 CK2 似乎是重要的靶激酶。通过应用抑制剂（例如 DMAT）抑制这些激酶可能代表未来 HCC 治疗的一种有前途的治疗方法。
