Kinetics of cyclocreatine and Na(+) cotransport in human breast cancer cells: mechanism of activity.
The growth-inhibitory effect of cyclocreatine (CCr) and the kinetics of CCr and Na(+) cotransport were investigated in MCF7 human breast cancer cells and its adriamycin-resistant subline with use of (31)P- and (23)Na-NMR spectroscopy. The growth-inhibitory effect in the resistant line occurred at a lower CCr concentration and was more pronounced than in the wild-type line. This correlated with an approximately 10-fold higher affinity of CCr to the transporter in the resistant line. The passive diffusion coefficient of CCr was also higher in the resistant line by three- to fourfold. The transport of CCr was accompanied by a rapid increase in intracellular Na(+). This increase was found to depend on the rate of CCr transport and varied differently with CCr concentration in the two cell lines. It is proposed that the cotransport of CCr and Na(+) followed by increased Na(+) concentration, together with the accumulation of the highly charged phosphocyclocreatine, are responsible for cell swelling and death.
Maril
N
N
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Degani
H
H
Rushkin
E
E
Sherry
A D
AD
Cohn
M
M
D001692:Biological Transport / Q000502:physiology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D003401:Creatine / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D003404:Creatinine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010758:Phosphorus; D012964:Sodium / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D010758:Phosphorus; C012260:cyclocreatine; D012964:Sodium; D003404:Creatinine; D003402:Creatine Kinase; D003401:Creatine