Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tibolone is a synthetic progestin with estrogenic and progestogenic properties, used to alleviate menopausal syndromes and for osteoporosis prophylaxis in postmenopausal women. However, only little data are available on tibolone and breast cancer risk and on the effects of tibolone on the cardiovascular system. Therefore, in the present in vitro study, we investigated the effect of tibolone on the growth of the human breast cancer cell line, MCF-7, and on the direct effects of tibolone on the vasculature, i.e. human female coronary endothelial and smooth muscle cells. In the breast cancer cell experiments, tibolone was examined alone and in the presence of 0.1 nM estradiol in the concentration range from 0.001 microM to 1 microM. Tibolone lead to significant cell growth in the concentration range of 0.01 micro M to 1 microM and was not able to inhibit estradiol-induced proliferation at the concentrations of 0.01 microM and 0.1 microM. In the vascular endothelial cell culture experiments, tibolone was tested at the concentrations 0.1 microM, 1 microM and 10 microM. Tibolone reduced the synthesis of endothelin as well as the concentrations of E-selectin, PAI-1 and pro-MMP-1. The magnitude of the effects on these markers varied and was in the range of 11%-42%. Concerning smooth muscle cells, tibolone elicited no changes in the proliferation compared to control values. These data suggest that tibolone does have tumour cell-growth promoting effects in vitro. However, tibolone can positively influence the synthesis of markers in cell cultures of human female coronary artery, which modulate vascular tone and which play a decisive role in the various stages of atherosclerosis. Drawing a clinical consequence from our experiments would result in not recommending the use of tibolone in postmenopausal women at high risk for breast cancer development until long-term controlled clinical studies have been performed on the effect of tibolone administration and breast cancer risk. Experimental studies, such as the present one, are useful to explore mechanisms, but clearly cannot replace clinical studies.
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PMID:Effects of tibolone on human breast cancer cells and human vascular coronary cells. 1255 24

Tibolone and its metabolites were evaluated on matrix metalloproteinase (MMP) expression in human endometrial stromal cells (HESCs) under the hypothesis that these steroids would act as progestins on MMP-1, -2, and -3 expression. After 7 days of priming and 24h experimental incubation of confluent cultured HESCs, 10(-7) M medroxyprogesterone acetate (P) reduced MMP-1 to 49+/-34% (p<0.05) and MMP-3 to 33+/-22% of basal levels (mean+/-S.E.M., p<0.05, n=5). Although HESCs were unaffected by 10(-8) M estradiol (E), E+P reduced MMP-1 and MMP-3 levels an additional 2.5-fold from P alone. Tibolone and Delta-4 tibolone were equivalent to E+P in inhibiting MMP-1 and MMP-3 output, whereas 10(-6)M of 3alpha-OH or 3beta-OH tibolone was required to elicit significant inhibition of both MMPs (p<0.05). By contrast, none of the treatments affected HESC-secreted MMP-2 output. The ELISA results were confirmed by Western blotting and by substrate gel zymography. Quantitative RT-PCR demonstrated corresponding changes in MMP-1 and MMP-3 mRNA levels. Inhibition of MMP-1 and MMP-3 expression by tibolone and Delta-4 tibolone is consistent with the metabolism of tibolone to Delta-4 tibolone, and subsequent binding of Delta-4 tibolone to the progesterone receptor. Since 3alpha-OH and 3beta-OH tibolone bind exclusively to the estrogen receptor, their inhibition of MMP-1 and MMP-3 suggests metabolism by HESCs to Delta-4 tibolone. These observations help to explain the paradox that the endometrium becomes atrophic after tibolone administration despite the persistence in the circulation of 3alpha-OH and 3beta-OH tibolone, but not tibolone or Delta-4 tibolone.
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PMID:Tibolone exerts progestational inhibition of matrix metalloproteinase expression in human endometrial stromal cells. 1680 36