Neutral endopeptidase (NEP) inhibitors - thiorphan, sialorphin, and its derivatives exert anti-proliferative activity towards colorectal cancer cells in vitro

Magdalena Mizerska-Kowalska , Joanna Kreczko-Kurzawa , Barbara Zdzisińska , Arkadiusz Czerwonka , Adrianna Sławińska-Brych , Zbigniew Maćkiewicz , Dawid Nidzworski

Abstract

Neutral endopeptidase (NEP) is an enzyme implicated in development of different tumors, e.g. colorectal cancer (CRC). In this study, the anti-cancer effects of NEP inhibitors, thiorphan (synthetic compound)and sialorphin (naturally occurring pentapeptide) on CRC cells were investigated. Moreover, we synthesized some derivatives of sialorphin (alanine scan analogues: AHNPR, QANPR, QHAPR, QHNAR; N-acetylated sialorphin; C-amidated sialorphin, and C-amidated alanine scan analogues) to examine the biological activity of these inhibitors on CRC cells. The cytotoxic activity of the NEP inhibitors against CRC cell lines (SW620 and LS180) and normal human fibroblasts (HSF) was evaluated. Additionally, the influence of NEP inhibitors on proliferation, cell cycle progression, induction of apoptosis, and the level of phosphorylation of MAP kinases and mTORC1 signaling pathway proteins in CRC cells were examined. The NEP inhibitors were non-cytotoxic to HSF cells; however, most of them slightly decreased the viability and inhibited proliferation of CRC cells. The N-acetylation or C-amidation of sialorphin or its alanine scan analogues resulted in decreased or abolished anti-proliferative activity of the NEP inhibitors towards the CRC cells. Additionally, thiorphan and sialorphin enhanced the anti-proliferative activity of other CRC-cell growth inhibitors (atrial natriuretic peptide-ANP and melphalan-MEL). The mechanisms involved in the anti-proliferative effects of the tested inhibitors were mediated via NEP and associated with induction of cell cycle arrest in the G0/G1 phase, increased activity of ERK1/2, and a reduced level of phosphorylation of mTOR (Ser2448), 4E-BP1, and p70S6K. However, the NEP inhibitors did not induce apoptosis in the CRC cells. These results have indicated that thiorphan and sialorphin or its derivatives AHNPR, QANPR, QHAPR, and QHNAR have the potential to be used as agents in treatment of patients with CRC.
Author Magdalena Mizerska-Kowalska
Magdalena Mizerska-Kowalska,,
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, Joanna Kreczko-Kurzawa (FCh / DMBt / LChBM)
Joanna Kreczko-Kurzawa,,
- Laboratory of Chemistry of Biological Macromolecules
, Barbara Zdzisińska
Barbara Zdzisińska,,
-
, Arkadiusz Czerwonka
Arkadiusz Czerwonka,,
-
, Adrianna Sławińska-Brych
Adrianna Sławińska-Brych,,
-
, Zbigniew Maćkiewicz (FCh / DMBt / LChBM)
Zbigniew Maćkiewicz,,
- Laboratory of Chemistry of Biological Macromolecules
, Dawid Nidzworski
Dawid Nidzworski,,
-
Journal seriesChemico-Biological Interactions, ISSN 0009-2797, (N/A 100 pkt)
Issue year2019
Vol307
Pages105-115
Publication size in sheets0.5
Keywords in Englishneutral endopeptidase inhibitors, colon cancer cells, cell cycle arrest, extracellular signal-regulated kinase 1 and 2, (ERK1/2), mammalian target of rapamycin (mTOR)
ASJC Classification3005 Toxicology; 2700 General Medicine
DOIDOI:10.1016/j.cbi.2019.04.033
URL https://doi.org/10.1016/j.cbi.2019.04.033
Languageen angielski
Score (nominal)100
ScoreMinisterial score = 100.0, 30-09-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.074; WoS Impact Factor: 2017 = 3.296 (2) - 2017=3.308 (5)
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