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

Scientific Reports
Rajesh Kumar GandhirajanSander Bekeschus

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 selecti...Continue Reading

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Citations

Apr 1, 2020·International Journal of Molecular Sciences·Lyubomir HaralambievMatthias B Stope
May 23, 2020·Advanced Science·Sander BekeschusAnke Schmidt
Jan 23, 2020·Der Hautarzt; Zeitschrift für Dermatologie, Venerologie, und verwandte Gebiete·L BoeckmannS Emmert
Feb 23, 2020·International Journal of Molecular Sciences·Gabriella Pasqual-MeloSander Bekeschus
Nov 7, 2019·Oxidative Medicine and Cellular Longevity·Angela Privat-MaldonadoSander Bekeschus
Jan 14, 2020·Redox Biology·Sander BekeschusRajesh Kumar Gandhirajan
Mar 7, 2021·Journal of Clinical Medicine·Miguel Mateu-SanzCristina Canal
Mar 27, 2021·British Journal of Cancer·Rajesh Kumar GandhirajanSander Bekeschus
May 1, 2021·Cancers·Hiromasa TanakaMounir Laroussi

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Methods Mentioned

BETA
FCS
flow cytometry
gene knockdown
transfection

Software Mentioned

GraphPad
prism
Harmony
Kaluza

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