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Intracellular HINT1-Assisted Hydrolysis of Nucleoside 5′-O-Selenophosphate Leads to the Release of Hydrogen Selenide That Exhibits Toxic Effects in Human Cervical Cancer Cells

Authors :
Agnieszka Krakowiak
Liliana Czernek
Marta Pichlak
Renata Kaczmarek
Source :
International Journal of Molecular Sciences, Vol 23, Iss 2, p 607 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

In this study, we present a new selenium derivative, 2′-deoxyguanosine-5′-O-selenophosphate (dGMPSe), synthesized by the oxathiaphospholane method and adapted here for the synthesis of nucleoside selenophosphates. Using biochemical assays (HPLC- and fluorescence-based), we investigated the enzymatic activity of HINT1 towards dGMPSe in comparison with the corresponding thiophosphate nucleoside, i.e., dGMPS. Both substrates showed similar kcat and a small difference in Km, and during the reactions the release of reducing agents such as H2Se and H2S were expected and detected. MTT viability assay and microscopic analysis showed that dGMPSe was toxic to HeLa cancer cells, and this cytotoxicity was due to the release of H2Se. The release of H2Se or H2S in the living cells after administration of dGMPSe and/or dGMPS, both without carrier and by electroporation, was observed using a fluorescence assay, as previously for NMPS. In conclusion, our comparative experiments with dGMPSe and dGMPS indicate that the HINT1 enzyme is capable of converting (d)NMPSe to (d)NMP and H2Se, both in vitro and intracellularly. Since the anticancer activity of various selenium compounds depends on the formation of hydrogen selenide, the actual inducer of cell death, we propose that selenium-containing nucleotides represent another option as novel compounds with anticancer therapeutic potential.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
23
Issue :
2
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.7ff879fb539a42b691cb416a6fb214ff
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms23020607