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 andNa⁺ cotransport were investigatedin MCF7 human breast cancer cells and its adriamycin-resistant sublinewith use of ³¹P- and²³Na-NMR spectroscopy. Thegrowth-inhibitory effect in the resistant line occurred at a lower CCrconcentration and was more pronounced than in the wild-type line. Thiscorrelated with an ~10-fold higher affinity of CCr to the transporterin the resistant line. The passive diffusion coefficient of CCr wasalso higher in the resistant line by three- to fourfold. The transportof CCr was accompanied by a rapid increase in intracellularNa⁺. This increase was found todepend on the rate of CCr transport and varied differently with CCrconcentration in the two cell lines. It is proposed that thecotransport 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.

     

Appearance of LH-receptors and LH-stimulable cyclic AMP accumulation in granulosa cells during follicular maturation in the rat ovary.

The number of receptors for human chorionic gonadotropin (hCG) was low in granulosa cells (GC) of follicles at 9.00 h on the day of metestrus (530 ± 150 sites/cell; mean ± S.E.) and gradually increased thereafter to reach a maximum at 21.00 h on the day of proestrus (24,300 ± 700). There was no significant difference in ¹²⁵I-hCG binding between GC collected before the preovulatory LH-surge and cells collected 7 h after the surge. LH-stimulable cyclic AMP accumulation was higher in GC collected 7 h after the surge than in GC collected before the surge or in GC from animals in which the LH-surge was blocked by treatment with Nembutal. Exogenous hCG (50 IU/rat) also failed to induce desensitization of LH-stimulable adenylate cyclase in GC collected 10 h after the injection. The results show (i) cyclic changes in the LH-receptor population of rat GC compatible with the concept that the receptor is induced by the estrogen and FSH surges of the preceding cycle, and (ii) failure of the preovulatory LH-surge to induce refractoriness of adenylate cyclase in rat GC in vivo.