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

Scientific Reports
Yousef M AlharbiManish S Patankar

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.

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Citations

Oct 22, 2020·Scientific Reports·Iñigo Arberas-JiménezJacob Lorenzo-Morales
Dec 22, 2020·BioMed Research International·Zhenhua YinWenyi Kang
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jiří BejčekSilvie Rimpelová

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Methods Mentioned

BETA
flow cytometry
X-ray

Software Mentioned

FlowJo
pClamp
10

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