Kinetics of cyclocreatine and Na1 cotransport in human breast cancer cells: mechanism of activity

Maril, Nimrod, Hadassa Degani, Edna Rushkin, A. Dean Sherry, and Mildred Cohn. Kinetics of cyclocreatine and Na1 cotransport in human breast cancer cells: mechanism of activity. Am. J. Physiol. 277 (Cell Physiol. 46): C708–C716, 1999.—The growth-inhibitory effect of cyclocreatine (CCr) and the kinetics of CCr and Na1 cotransport were investigated in MCF7 human breast cancer cells and its adriamycin-resistant subline with use of 31Pand 23Na-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 ,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 threeto fourfold. The transport of CCr was accompanied by a rapid increase in intracellular Na1. 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 Na1 followed by increased Na1 concentration, together with the accumulation of the highly charged phosphocyclocreatine, are responsible for cell swelling and death.