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.
Mulvaney
P T
PT
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Stracke
M L
ML
Nam
S W
SW
Woodhouse
E
E
O'Keefe
M
M
Clair
T
T
Liotta
L A
LA
Khaddurah-Daouk
R
R
Schiffmann
E
E
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