Endocrine Abstracts (2001) 2 P38

Effect of metallopeptidase inhibitors and growth factors on MCF-7 cell proliferation

M Ahmed, MP Schrey & DC Parish

Endocrinology and Metabolic Medicine, Imperial College Faculty of Medicine, London, UK.

Regulatory peptides are known to have a role in tumour growth. Local peptide concentrations will be affected by their proteolytic release from precursors, together with the rate of their proteolytic degradation. In this study three inhibitors of proteolysis were examined, Captopril, an ACE inhibitor, Thiorphan an inhibitor of Neutral Endopeptidase and Phosphoramidon which inhibits both Neutral Endopeptidase and also Endothelin Converting Enzyme (ECE). The effect of these inhibitors on the proliferation of the epithelial breast cancer cell line, MCF-7, was examined using a 96-well plate format (Cell Proliferation Assay, Promega). MCF-7 cells (5,000/well) were incubated with these inhibitors at a range of concentration from 0.1-10 uM for 3-6 days and no significant effects were observed. Cell proliferation was stimulated with either PDGF or IGF-1 (10 ng/ml) or EGF (100ng/ml). The cells were incubated with both a growth factor and an inhibitor (10uM) for 4 days. Captopril reduced growth factor stimulated cell proliferation to 69% of control cell numbers for PDGF and 60% for IGF-1. Phosphoramidon reduced EGF stimulated proliferation (to 50%) PDGF-stimulated to 60% and IGF-1 stimulated to 40%. Thiorphan had no significant effects on Growth Factor stimulated proliferation.Captopril may be preventing the local production of Angiotensin II. There is a known local Renin-Angiotensin system in the breast which could affect tumour growth. Since Phosphoramidon but not Thiorphan affected cell growth it is more likely to act through ECE rather than Neutral Endopeptidase. The expression of either the peptidases or their substrates may be regulated by these growth factors and these peptides could contribute to the stimulation of proliferation induced by the growth factors.

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