Mammary renin-angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer.

Angiotensin II in particular and/or the local renin-angiotensin system in general could have an important role in epithelial tissue growth and modelling; therefore, it is possible that it may be involved in breast cancer. In this sense, previous works of our group showed a predominating role of angiotensin II in tumoral tissue obtained from women with breast cancer. However, although classically angiotensin II has been considered the main effector peptide of the renin-angiotensin system cascade, several of its catabolism products such as angiotensin III and angiotensin IV also possess biological functions. These peptides are formed through the activity of several proteolytic regulatory enzymes of the aminopeptidase type, also called angiotensinases. The aim of this work was to analyse several specific angiotensinase activities involved in the renin-angiotensin system cascade in mammary tissue from control rats and from rats with mammary tumours induced by N-methyl-nitrosourea (NMU), which may reflect the functional status of their target peptides under the specific conditions brought about by the tumoural process. The results show that soluble and membrane-bound specific aspartyl aminopeptidase activities and membrane-bound glutamyl aminopeptidase activity increased in mammary tissue from NMU-treated animals and soluble aminopeptidase N and aminopeptidase B activities significantly decreased in mammary tissue from NMU-treated rats. These changes support the existence of a local mammary renin-angiotensin system and that this system and its putative functions in breast tissue could be altered by the tumour process, in which we suggest a predominant role of angiotensin III. All described data about the renin-angiotensin system in mammary tissue support the idea that it must be involved in normal breast tissue functions, and its disruption could be involved in one or more steps of the carcinogenesis process.

Ovarian renin--angiotensin system-regulating aminopeptidases are involved in progesterone overproduction in rats with mammary tumours induced by N-methyl nitrosourea.

UNLABELLED: A local renin-angiotensin system (RAS) has been found in ovary. This ovarian RAS may regulate ovarian steroidogenesis. Ample studies show that the ovarian hormones estradiol (E2) and progesterone (P) are strongly implicated in the development of breast cancer. MATERIALS AND METHODS: The aim of the present work was to elucidate if alterations in ovarian RAS, analyzed through their proteolytic regulatory enzymes aminopeptidase A (APA), B (APB) and N (APN), could be responsible for an altered steroidogenesis in rats with mammary tumours induced by N-methyl nitrosourea (NMU). RESULTS: We describe here a highly significant increase of serum P levels in NMU-treated rats, concomitantly with an increase in ovarian aspartyl and glutamyl aminopeptidase activities (named together as APA activity). Moreover, we did not find changes in APB or APN activities, suggesting an increased metabolism from Ang II to Ang III and a decreased catabolism of Ang III. CONCLUSION: The relationship between ovarian RAS and P overproduction in a rat model of mammary carcinogenesis indicates ovarian RAS as a new potential target in breast cancer therapy.

Melatonin induces apoptosis in human neuroblastoma cancer cells.

Low concentrations (nanomolar) of melatonin had been previously shown to inhibit cell proliferation in several cancer cell lines as well as in experimental animal models. Additionally, cell growth inhibition and differentiation of prostate cancer cell lines by high concentrations (micromolar to millimolar) of melatonin have been recently reported. In the present paper, we show the induction of apoptosis by high doses of melatonin in the human neuroblastoma cell line SK-N-MC. We found accumulation of cells in the G2/M cell cycle phase and induction of cellular death, measured as lactate dehydrogenase (LDH) released into the culture medium, under millimolar concentration of melatonin. Apoptosis was evaluated using 4,6-diamidino-2-phenylindole staining, DNA gel electrophoresis, electron microscopy, and annexin V binding. Apoptosis progressed through the classical pathway, which involves caspase-3 activation. Cell death was dose and time-dependent; the lowest effective concentration of melatonin was 100 microm. Treatment with 1 mm melatonin for 6 days induced cell death in 75% of the cells. This novel finding shows that a nontoxic natural indoleamine may be potential therapy for some types of human neuroblastomas.