Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production

Abstract The development of targeted drugs for the treatment of cancer remains an unmet medical need. This study was designed to investigate the mechanism underlying breast cancer cell growth suppression caused by fused isoselenazolium salts. The ability to suppress the proliferation of malignant an...

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Autores principales:	Marina Makrecka-Kuka, Pavels Dimitrijevs, Ilona Domracheva, Kristaps Jaudzems, Maija Dambrova, Pavel Arsenyan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9530a9b4b9d8471ea4c2facbb29d7c84
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spelling	oai:doaj.org-article:9530a9b4b9d8471ea4c2facbb29d7c842021-12-02T16:18:05ZFused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production10.1038/s41598-020-78620-82045-2322https://doaj.org/article/9530a9b4b9d8471ea4c2facbb29d7c842020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78620-8https://doaj.org/toc/2045-2322Abstract The development of targeted drugs for the treatment of cancer remains an unmet medical need. This study was designed to investigate the mechanism underlying breast cancer cell growth suppression caused by fused isoselenazolium salts. The ability to suppress the proliferation of malignant and normal cells in vitro as well as the effect on NAD homeostasis (NAD+, NADH, and NMN levels), NAMPT inhibition and mitochondrial functionality were studied. The interactions of positively charged isoselenazolium salts with the negatively charged mitochondrial membrane model were assessed. Depending on the molecular structure, fused isoselenazolium salts display nanomolar to high micromolar cytotoxicities against MCF-7 and 4T1 breast tumor cell lines. The studied compounds altered NMN, NAD+, and NADH levels and the NAD+/NADH ratio. Mitochondrial functionality experiments showed that fused isoselenazolium salts inhibit pyruvate-dependent respiration but do not directly affect complex I of the electron transfer system. Moreover, the tested compounds induce an immediate dramatic increase in the production of reactive oxygen species. In addition, the isoselenazolothiazolium derivative selectively binds to cardiolipin in a liposomal model. Isoselenazolium salts may be a promising platform for the development of potent drug candidates for anticancer therapy that impact mitochondrial pyruvate-dependent metabolism in breast cancer cells.Marina Makrecka-KukaPavels DimitrijevsIlona DomrachevaKristaps JaudzemsMaija DambrovaPavel ArsenyanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marina Makrecka-Kuka Pavels Dimitrijevs Ilona Domracheva Kristaps Jaudzems Maija Dambrova Pavel Arsenyan Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production
description	Abstract The development of targeted drugs for the treatment of cancer remains an unmet medical need. This study was designed to investigate the mechanism underlying breast cancer cell growth suppression caused by fused isoselenazolium salts. The ability to suppress the proliferation of malignant and normal cells in vitro as well as the effect on NAD homeostasis (NAD+, NADH, and NMN levels), NAMPT inhibition and mitochondrial functionality were studied. The interactions of positively charged isoselenazolium salts with the negatively charged mitochondrial membrane model were assessed. Depending on the molecular structure, fused isoselenazolium salts display nanomolar to high micromolar cytotoxicities against MCF-7 and 4T1 breast tumor cell lines. The studied compounds altered NMN, NAD+, and NADH levels and the NAD+/NADH ratio. Mitochondrial functionality experiments showed that fused isoselenazolium salts inhibit pyruvate-dependent respiration but do not directly affect complex I of the electron transfer system. Moreover, the tested compounds induce an immediate dramatic increase in the production of reactive oxygen species. In addition, the isoselenazolothiazolium derivative selectively binds to cardiolipin in a liposomal model. Isoselenazolium salts may be a promising platform for the development of potent drug candidates for anticancer therapy that impact mitochondrial pyruvate-dependent metabolism in breast cancer cells.
format	article
author	Marina Makrecka-Kuka Pavels Dimitrijevs Ilona Domracheva Kristaps Jaudzems Maija Dambrova Pavel Arsenyan
author_facet	Marina Makrecka-Kuka Pavels Dimitrijevs Ilona Domracheva Kristaps Jaudzems Maija Dambrova Pavel Arsenyan
author_sort	Marina Makrecka-Kuka
title	Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production
title_short	Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production
title_full	Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production
title_fullStr	Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production
title_full_unstemmed	Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production
title_sort	fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ros production
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/9530a9b4b9d8471ea4c2facbb29d7c84
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Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production

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