Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells

Abstract The Na+/K+-ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative ph...

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Autores principales:	Yousef Alharbi, Arvinder Kapur, Mildred Felder, Lisa Barroilhet, Timothy Stein, Bikash R. Pattnaik, Manish S. Patankar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/711cb0ad0da842b3aed61841711db73e
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spelling	oai:doaj.org-article:711cb0ad0da842b3aed61841711db73e2021-12-02T15:09:31ZPlumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells10.1038/s41598-019-47261-x2045-2322https://doaj.org/article/711cb0ad0da842b3aed61841711db73e2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-47261-xhttps://doaj.org/toc/2045-2322Abstract The Na+/K+-ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative phosphorylation. As a result, plumbagin treatment results in decreased production of ATP and a rapid increase in intracellular oxygen radicals. We show that plumbagin induces apoptosis in canine cancer cells via oxidative stress. We use this model to test the effect of oxidative stress on NKA activity. Using whole-cell patch-clamp electrophysiology we demonstrate that short-term exposure (4 min) to plumbagin results in 48% decrease in outward current at +50 mV. Even when exogenous ATP was supplied to the cells, plumbagin treatment resulted in 46% inhibition of outward current through NKA at +50 mV. In contrast, when the canine cancer cells were pre-treated with the oxygen radical scavenger, N-acetylcysteine, the NKA inhibitory activity of plumbagin was abrogated. These experiments demonstrate that the oxidative stress-causing agents such as plumbagin and its analogues, are a novel avenue to regulate NKA activity in tumors.Yousef AlharbiArvinder KapurMildred FelderLisa BarroilhetTimothy SteinBikash R. PattnaikManish S. PatankarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-10 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yousef Alharbi Arvinder Kapur Mildred Felder Lisa Barroilhet Timothy Stein Bikash R. Pattnaik Manish S. Patankar Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells
description	Abstract The Na+/K+-ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative phosphorylation. As a result, plumbagin treatment results in decreased production of ATP and a rapid increase in intracellular oxygen radicals. We show that plumbagin induces apoptosis in canine cancer cells via oxidative stress. We use this model to test the effect of oxidative stress on NKA activity. Using whole-cell patch-clamp electrophysiology we demonstrate that short-term exposure (4 min) to plumbagin results in 48% decrease in outward current at +50 mV. Even when exogenous ATP was supplied to the cells, plumbagin treatment resulted in 46% inhibition of outward current through NKA at +50 mV. In contrast, when the canine cancer cells were pre-treated with the oxygen radical scavenger, N-acetylcysteine, the NKA inhibitory activity of plumbagin was abrogated. These experiments demonstrate that the oxidative stress-causing agents such as plumbagin and its analogues, are a novel avenue to regulate NKA activity in tumors.
format	article
author	Yousef Alharbi Arvinder Kapur Mildred Felder Lisa Barroilhet Timothy Stein Bikash R. Pattnaik Manish S. Patankar
author_facet	Yousef Alharbi Arvinder Kapur Mildred Felder Lisa Barroilhet Timothy Stein Bikash R. Pattnaik Manish S. Patankar
author_sort	Yousef Alharbi
title	Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells
title_short	Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells
title_full	Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells
title_fullStr	Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells
title_full_unstemmed	Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells
title_sort	plumbagin-induced oxidative stress leads to inhibition of na+/k+-atpase (nka) in canine cancer cells
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/711cb0ad0da842b3aed61841711db73e
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Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells

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