Choline kinase (ChoK) catalyzes the phosphorylation of choline by ATP in the presence of Mg2+ to yield phosphocholine (PCho) and ADP. In humans, ChoKα1 and ChoKα2 derive from a single gene (chk-α) by alternative splicing. EB-3D, a potent and selective ChoKα inhibitor, shows an IC50 of 1 μM for human ChoKα1. In a panel of nine different human tumor-cell lines, EB-3D offered excellent antiproliferative activities against all cell lines with GI50 values ranging from 0.027 to 0.12 μM. The cell viability in the presence of EB-3D was also evaluated in Jurkat, HeLa and MDA-MB-231 cell lines. EB-3D significantly inhibited cell growth in three cell lines in a concentration-dependent manner. EB-3D induced a G1 arrest of the cell cycle, which occurred in a concentration-dependent manner in the three cell lines tested (Jurkat, MCF-7 and MDA-MB-231). Together with the G1 increase, a concomitant reduction was found in the S phase. Further, EB-3D at different concentrations after 72 h of incubation induced a modest increment in apoptotic cells only in Jurkat cells[1]. Experimental metastasis models obtained after the iv injection of murine E0771 or human MDA-MB-231 cells were treated with EB-3D at the dose of 2.5 mg/kg. After lung removal, the number of macrometastases as well as of micrometastases was significantly reduced in treated mice when compared with control lungs. In addition, a significant reduction of resected lung weight was appreciable after EB-3D treatment[2].
作用机制
The 1-benzyl-4-(dimethylamino)pyridinium fragment of EB-3D performs a strong π-cation interaction with the Cho binding site[1].
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