Aminopeptidase N Inhibitors as Pointers for Overcoming Antitumor Treatment Resistance

Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress...

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Vydané v:International journal of molecular sciences Ročník 23; číslo 17; s. 9813
Hlavní autori: Farsa, Oldřich, Ballayová, Veronika, Žáčková, Radka, Kollar, Peter, Kauerová, Tereza, Zubáč, Peter
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Basel MDPI AG 01.09.2022
MDPI
Predmet:
Amino acids
Apoptosis
Clinical trials
Enzymes
Kidney cancer
Lung cancer
Regression analysis
Treatment resistance
Tumor necrosis factor-TNF
ISSN:1422-0067, 1661-6596, 1422-0067
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Shrnutí:Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23179813