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 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.

Medical Gas Plasma Jet Technology Targets Murine Melanoma in an Immunogenic Fashion

“…[ 3 ] The evidence in the field of medical gas plasma research points to the importance of ROS in mediating plasma‐induced tumor cell death. [ 8 ] The current concept is that these plasma‐derived ROS generate secondary ROS and oxidation products that accumulate inside tumor cells, leading to mitochondrial damage [ 24 ] and pro‐apoptotic signaling. [ 25 ] Exposure of tumor cells to plasma‐derived ROS is accompanied by changes in the release of chemokines and cytokines, [ 26 ] several immunomodulatory receptors, [ 27 ] and upregulation of markers of the immunogenic cancer cell death (ICD) [ 28 ] and cellular senescence.…”

The HIPPO Transducer YAP and Its Targets CTGF and Cyr61 Drive a Paracrine Signalling in Cold Atmospheric Plasma-Mediated Wound Healing

“…H 2 O 2 is an important second messenger that is generated by CAP which triggers the release of growth factors during the wound healing process and has been shown to increase keratinocyte viability and migration in wound models [46]. Previous studies have revealed an increase in H 2 O 2 in response to increasing CAP treatments [47]. Intracellular ROS levels also increase in keratinocytes after plasma treat-ment [48,49].…”

Combination Treatment with Cold Physical Plasma and Pulsed Electric Fields Augments ROS Production and Cytotoxicity in Lymphoma

“…First discovered as a new tool for disinfection and wound healing [12][13][14], plasma also demonstrates cytotoxicity towards cancer cells [15][16][17]. A range of cellular responses have been found, including apoptosis, growth inhibition, cell cycle arrest, as well as cytoskeletal and mitochondrial damage [18][19][20]. The exact mechanism of plasma-induced apoptosis seems to be cell line dependent, varying from Table 1.…”