Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction

Abstract Despite striking advances in the treatment of metastasized melanoma, the disease is often still fatal. Attention is therefore paid towards combinational regimens. Oxidants endogenously produced in mitochondria are currently targeted in pre-clinical and clinical studies. Cytotoxic synergism...

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Autores principales:	Rajesh Kumar Gandhirajan, Katrin Rödder, Yana Bodnar, Gabriella Pasqual-Melo, Steffen Emmert, Corinne E. Griguer, Klaus-Dieter Weltmann, Sander Bekeschus
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e7765252a4bf4fd98c1c2fb12bede776
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spelling	oai:doaj.org-article:e7765252a4bf4fd98c1c2fb12bede7762021-12-02T15:08:44ZCytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction10.1038/s41598-018-31031-22045-2322https://doaj.org/article/e7765252a4bf4fd98c1c2fb12bede7762018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-31031-2https://doaj.org/toc/2045-2322Abstract Despite striking advances in the treatment of metastasized melanoma, the disease is often still fatal. Attention is therefore paid towards combinational regimens. Oxidants endogenously produced in mitochondria are currently targeted in pre-clinical and clinical studies. Cytotoxic synergism of mitochondrial cytochrome c oxidase (CcO) inhibition in conjunction with addition of exogenous oxidants in 2D and 3D melanoma cell culture models were examined. Murine (B16) and human SK-MEL-28 melanoma cells exposed to low-dose CcO inhibitors (potassium cyanide or sodium azide) or exogenous oxidants alone were non-toxic. However, we identified a potent cytotoxic synergism upon CcO inhibition and plasma-derived oxidants that led to rapid onset of caspase-independent melanoma cell death. This was mediated by mitochondrial dysfunction induced by superoxide elevation and ATP depletion. This observation was validated by siRNA-mediated knockdown of COX4I1 in SK-MEL-28 cells with cytotoxicity in the presence of exogenous oxidants. Similar effects were obtained with ADDA 5, a recently identified specific inhibitor of CcO activity showing low toxicity in vivo. Human keratinocytes were not affected by this combinational treatment, suggesting selective effects on melanoma cells. Hence, targeting mitochondrial CcO activity in conjunction with exogenous pro oxidant therapies may constitute a new and effective melanoma treatment modality.Rajesh Kumar GandhirajanKatrin RödderYana BodnarGabriella Pasqual-MeloSteffen EmmertCorinne E. GriguerKlaus-Dieter WeltmannSander BekeschusNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rajesh Kumar Gandhirajan Katrin Rödder Yana Bodnar Gabriella Pasqual-Melo Steffen Emmert Corinne E. Griguer Klaus-Dieter Weltmann Sander Bekeschus Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
description	Abstract Despite striking advances in the treatment of metastasized melanoma, the disease is often still fatal. Attention is therefore paid towards combinational regimens. Oxidants endogenously produced in mitochondria are currently targeted in pre-clinical and clinical studies. Cytotoxic synergism of mitochondrial cytochrome c oxidase (CcO) inhibition in conjunction with addition of exogenous oxidants in 2D and 3D melanoma cell culture models were examined. Murine (B16) and human SK-MEL-28 melanoma cells exposed to low-dose CcO inhibitors (potassium cyanide or sodium azide) or exogenous oxidants alone were non-toxic. However, we identified a potent cytotoxic synergism upon CcO inhibition and plasma-derived oxidants that led to rapid onset of caspase-independent melanoma cell death. This was mediated by mitochondrial dysfunction induced by superoxide elevation and ATP depletion. This observation was validated by siRNA-mediated knockdown of COX4I1 in SK-MEL-28 cells with cytotoxicity in the presence of exogenous oxidants. Similar effects were obtained with ADDA 5, a recently identified specific inhibitor of CcO activity showing low toxicity in vivo. Human keratinocytes were not affected by this combinational treatment, suggesting selective effects on melanoma cells. Hence, targeting mitochondrial CcO activity in conjunction with exogenous pro oxidant therapies may constitute a new and effective melanoma treatment modality.
format	article
author	Rajesh Kumar Gandhirajan Katrin Rödder Yana Bodnar Gabriella Pasqual-Melo Steffen Emmert Corinne E. Griguer Klaus-Dieter Weltmann Sander Bekeschus
author_facet	Rajesh Kumar Gandhirajan Katrin Rödder Yana Bodnar Gabriella Pasqual-Melo Steffen Emmert Corinne E. Griguer Klaus-Dieter Weltmann Sander Bekeschus
author_sort	Rajesh Kumar Gandhirajan
title	Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
title_short	Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
title_full	Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
title_fullStr	Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
title_full_unstemmed	Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
title_sort	cytochrome c oxidase inhibition and cold plasma-derived oxidants synergize in melanoma cell death induction
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e7765252a4bf4fd98c1c2fb12bede776
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Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction

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