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

Rajesh Kumar Gandhirajan; Katrin Rödder; Yana Bodnar; Gabriella Pasqual-Melo; Steffen Emmert; Corinne E Griguer; Klaus-Dieter Weltmann; Sander Bekeschus

doi:10.1038/s41598-018-31031-2

Back

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

Journal article

Open access

Peer reviewed

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

Rajesh Kumar Gandhirajan, Katrin Rödder, Yana Bodnar, Gabriella Pasqual-Melo, Steffen Emmert, Corinne E Griguer, Klaus-Dieter Weltmann and Sander Bekeschus

Scientific reports, Vol.8(1), pp.12734-12

12/01/2018

DOI: 10.1038/s41598-018-31031-2

PMCID: PMC6109085

PMID: 30143716

Files and links (1)

url

https://doi.org/10.1038/s41598-018-31031-2View

Published (Version of record) Open Access

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.

Details

Title: Subtitle: Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
Creators: Rajesh Kumar Gandhirajan - Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Katrin Rödder - Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Yana Bodnar - Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Gabriella Pasqual-Melo - Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Steffen Emmert - University Medical Center Rostock, Clinic for Dermatology and Venerology, Strempelstr. 13, 18057 Rostock, Germany
Corinne E Griguer - University of Birmingham, Department of Neurosurgery, 1670 University Boulevard, Birmingham, Alabama 35233 USA
Klaus-Dieter Weltmann - Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Sander Bekeschus - Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Resource Type: Journal article
Publication Details: Scientific reports, Vol.8(1), pp.12734-12
DOI: 10.1038/s41598-018-31031-2
PMID: 30143716
PMCID: PMC6109085
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Publisher: Nature Publishing Group UK; London
Language: English
Date published: 12/01/2018
Academic Unit: Radiation Oncology
Record Identifier: 9984047764302771

Metrics

21 Record Views

41 Times Cited - Web of Science