In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery.
Transformation by some oncogenes is associated with increased activity of choline kinase (ChoK), resulting in elevated constitutive levels of phosphorylcholine, a proposed second messenger required for DNA synthesis induced by growth factors. Here we describe the characterization of ChoK inhibitors with antiproliferative properties against human tumor-derived cell lines. The new molecules were tolerated in mice at doses that showed in vivo antitumor activity against human tumor xenografts derived from HT-29 and A431 cell lines implanted s.c. in nude mice. This first generation of inhibitors provides in vivo evidence that blockade of phosphorylcholine production is a valid strategy for the development of new anticancer agents, opening a new avenue for the development of antitumor drugs with a novel mechanism of action.
Hernández-Alcoceba
R
R
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Fernández
F
F
Lacal
J C
JC
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D002797:Choline Kinase