Cyclocreatine inhibits stimulated motility in tumor cells possessing creatine kinase.
Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine), an analog of creatine and a substrate for creatine kinase (EC 2.7.3.2), inhibits the stimulated motility of tumor cells which possess creatine kinase. A2058-055 human melanoma cells, transfected with a creatine kinase gene, showed an 80-90% reduction in chemotactic response to type IV collagen when incubated overnight in the presence of 10 mM cyclocreatine (p < 0.0001 for n = 8 experiments). This inhibitory effect of cyclocreatine can be partially reversed by addition of creatine to the overnight cell treatment. Non-transfected cells, with very low levels of creatine kinase, were not significantly inhibited. Further experiments utilizing type IV collagen as attractant demonstrated that cyclocreatine inhibited the chemokinetic (91%) and the haptotactic (73%) responses and the in vitro invasion of A2058-055 cells through Matrigel-coated membranes (88%). In addition, motility stimulation of A2058-055 cells by either autotaxin or fibronectin was markedly inhibited by cyclocreatine. DU-145 prostatic tumor cells, which express endogenous creatine kinase, also have a reduced motility response to either autotaxin or epidermal growth factor induced motility in the presence of cyclocreatine.
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
P T
PT
Mulvaney
M L
ML
Stracke
S W
SW
Nam
E
E
Woodhouse
M
M
O'Keefe
T
T
Clair
L A
LA
Liotta
R
R
Khaddurah-Daouk
E
E
Schiffmann
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D002633:Chemotaxis; D002945:Cisplatin / Q000494:pharmacology*; D003401:Creatine / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism*; D003404:Creatinine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000473:pathology; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; C012260:cyclocreatine; D003404:Creatinine; D003402:Creatine Kinase; D003401:Creatine; D002945:Cisplatin