Abstract
The selective in vitro anti-tumor mechanisms of cold atmospheric plasma (CAP) and plasma-activated media (PAM) follow a sequential multi-step process. The first step involves the formation of primary singlet oxygen (1O2) through the complex interaction between NO2− and H2O2.1O2 then inactivates some membrane-associated catalase molecules on at least a few tumor cells. With some molecules of their protective catalase inactivated, these tumor cells allow locally surviving cell-derived, extracellular H2O2 and ONOO─ to form secondary 1O2. These species continue to inactivate catalase on the originally triggered cells and on adjacent cells. At the site of inactivated catalase, cell-generated H2O2 enters the cell via aquaporins, depletes glutathione and thus abrogates the cell’s protection towards lipid peroxidation. Optimal inactivation of catalase then allows efficient apoptosis induction through the HOCl signaling pathway that is finalized by lipid peroxidation. An identical CAP exposure did not result in apoptosis for nonmalignant cells. A key conclusion from these experiments is that tumor cell-generated RONS play the major role in inactivating protective catalase, depleting glutathione and establishing apoptosis-inducing RONS signaling. CAP or PAM exposure only trigger this response by initially inactivating a small percentage of protective membrane associated catalase molecules on tumor cells.
Highlights
Tumor cells escape this apoptotic signaling primarily through expression of membrane-associated catalase[9,10,11,12,13]
The strong inhibitory effect of HIS added at two minutes after cold atmospheric plasma (CAP) treatment, demonstrates that 1O2 directly derived from CAP cannot be the major responsible agent, as 1O2 has an extremely short life time in the range of microseconds
The percentages of apoptotic cells were determined after 4.5 h. These results show that CAP-mediated apoptosis induction in tumor cells involves a very fast 1O2 - and ONOO−-dependent process, as well as longer-lasting processes in which superoxide anions and aquaporins are involved
Summary
Tumor cells escape this apoptotic signaling primarily through expression of membrane-associated catalase[9,10,11,12,13]. Www.nature.com/scientificreports catalase is a potentially attractive way to re-activate intercellular RONS-dependent apoptosis-inducing signaling[5,6,9,14]. It has been established that generation of singlet delta O2 (1O2) outside the cell membrane is capable of selectively inactivating membrane associated catalase, thereby re-activating intercellular RONS-driven apoptosis-inducing signaling[15]. A few reports claimed nonselective apoptosis-inducing effects of CAP or PAM (reviewed in refs[17,21]; please find detailed references in Supplementary Material). It has been suggested that this discrepancy might be resolved by standardization of CAP and PAM doses and composition[21]
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