Adenine nucleotides (ADP > ATP) greatly enhance Ca*+ uptake and retention in rat brain mitochondria. In the presence of both spermine and ADP, brain mitochondria sequester Ca *+ down to cellular free Ca2+ levels, suggesting a role for mitochondria in modulating Ca2+ cycles in brain cells. Analysis of the effects of various inhibitors on Ca2+ uptake and efflux suggest that locking the ADP/ATP translocator in its M-state stimulates electrogenic Ca*+ uptake and, to a lesser extent, inhibits Ca*+ efflux. It is suggested that this effect is due to a modulation of the surface charge on the M-side which enhances Ca2+ dissociation from the carriers.
Several studies have supported the idea that LH-releasing hormone (LHRH) antagonists have a direct effect on mammary tumor cells. In this study, we have evaluated the potential role of the insulin-like growth factors (IGFs) on the growth of MCF-7 mammary tumor cells and the effect of LHRH analogs on IGF action. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3 times more potent than IGF-II and 30 times more potent than insulin, suggesting that the effects of these growth factors are mediated by the IGF-I receptor. IGFs released by MCF-7 cells were measured by specific RIA after acid extraction and chromatography, so as to avoid the interference of IGF-binding proteins. MCF-7 cells secreted IGF-II, but not IGF-I. Estradiol (10(-9) mol/L) stimulated IGF-II release; this release preceded the effect of estradiol on cell growth. The LHRH antagonist [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10] LHR H (SB-75, CETRORELIX) inhibited basal, estrogen-induced, and IGF-induced growth. Moreover, this antagonist almost completely inhibited IGF-II release from MCF-7 cells. This effect preceded the inhibition of tumor cell growth. We conclude that a LHRH antagonist can inhibit the growth of breast tumors by interfering with the autocrine action of IGF-II and by directly inhibiting the growth stimulatory effect of IGFs.
The role of spironolactone in the aetiology of gynaecomastia was examined in terms of its ability to bind to the oestrogen receptor in cytosol, to cause specific oestrogenic effects in the absence of endogenous oestrogen and to be antioestrogenic in the presence of oestradiol. Tamoxifen, a non-steroidal antioestrogen, was chosen as an internal standard for comparison. Spironolactone and tamoxifen competitively inhibited the binding of oestradiol-17beta to its receptor in uterine and mammary cytosol, with inhibition constants of 2 x 10(-5) and 1 x 10(-7) mol/l respectively. To measure oestrogenic or antioestrogenic effects of the drugs five indices believed to be specific markers for oestrogen action were studied: uterine to body weight ratio, uterine protein content, oestradiol receptor in cytosol, progesterone receptor in cytosol and uterine peroxidase activity. Spironolactone, when administered for 3 successive days (40 microgram/day) to immature female rats, increased all of the five indices of oestrogen agonistic activity. The oestrogen-antagonistic properties of the drug were evaluated by comparing the oestradiol-injected group (5 microgram) to the oestradiol + spironolactone-injected group. A decrease was noted in all indices measured except for progesterone receptors in cytosol. Spironolactone appeared to be very similar to tamoxifen in its action both as an oestrogen and as an antioestrogen. The antioestrogenic effect of spironolactone cannot be explained by previously proposed mechanisms of action for the drug such as decreased synthesis of testosterone or inhibition of dihydrotestosterone binding to its receptor. These results suggest that spironolactone-induced gynaecomastia may be modulated by its action at both the oestrogen and dihydrotestosterone receptor in cytosol.
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