Abstract
Angiotensin-(1 - 7) [Ang-(1 - 7)] is an endogenous heptapeptide hormone of the renin-angiotensin system that has antiproliferative properties. The aim of this work was to evaluate the anti-proliferative and pro-apoptotic properties of Ang-(1 - 7) and of Ang-(1 - 7)-substituents 9-fluorenylmethyloxycarbonyl (Fmoc) e Ang II-derivatives containing the TOAC (2,2,6,6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid) in normal (MCF10A) and in tumoral (MCF7) epithelial mammary cell lines. Both cell lines received an hCG and angiotensin peptides 24-hour treatment, in combination or alone followed by cell viability, apoptosis and cell cycle assays performed by flow cytometer (GUAVA). After hCG, Ang-(1 - 7), hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments, MCF7 displayed cell viability decrease and mid-apoptosis increase. We also observed cell viability decrease in MCF10A after Ang-(1 - 7), Ang-(1 - 7) Fmoc and hCG + AngII Toac treatments. These cells had an increase in late apoptosis and necrosis after AngII Toac, hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments. Regarding the cell cycle analysis, we did not observed any changes in cell cycle phases. In summary, cell viability was decreased and apoptosis (initial, mid and late) was increased after hCG and/or Ang-(1 - 7) peptides treatments. These results point out hCG and Ang-(1 - 7) as effective compounds to inhibit cell proliferation, since they decrease cell viability and increase apoptosis in both normal and in tumoral breast cells, being the effect more pronounced in the tumoral cell line. Our results support the idea of investigating more closely the putative use of these compounds as novel therapeutic agents for breast cancer.
Highlights
Breast cancer is the most common cancer among American women, except for skin cancers
Angiotensin II (Ang II)-TOAC, an Ang II analogue containing the TOAC (2,2,6,6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid) spin label synthesized by solid phase methodology [23] and Ang-(1 - 7)-FMOC, an Ang-(1 - 7) analogue containing the FMOC (9-fluorenylmethyloxycarbonyl) group was used for protection of the amine function [24]
MCF-7 cells showed cell viability decrease while the mid-apoptosis increased after Ang-(1 - 7), Ang-(1 - 7)FMOC and Human Chorionic Gonadotropin (hCG) + Ang II-TOAC treatments (Figure 1(a))
Summary
Breast cancer is the most common cancer among American women, except for skin cancers. The proteolytic cascade of the RAS begins with the release of renin (REN), an aspartyl protease which cleaves angiotensinogen (AGT) produces Angiotensin I (Ang I), which is hydrolyzed by angiotensin converting enzyme (ACE) and releases Angiotensin II (Ang II); this octapeptide ex- JCT. Recent studies have shown that at a local tissue level, the components of the RAS influence tumor growth by changing its microenvironment [6,7]. Most studies have shown that this Ang(1 - 7) exerts its physiologic effects probably through activation of a unique G protein-coupled Ang-(1 - 7) [AT (1 - 7)] receptor encoded by the mas oncogene (mas1) [22]
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