The Plasma-Induced Leukemia Cell Death is Dictated by the ROS Chemistry and the HO-1/CXCL8 Axis

Cold physical plasma-derived reactive oxygen specie (ROS) inactivate cells, which might be beneficial in oncology. However, several aspects of plasma oncotherapy remain elusive. These include the identification of an ROS composition with maximum toxicity and the molecular mechanisms that govern the degree of plasma-induced cell death. Using two human leukemia cell lines and the plasma jet kINPen, we identified Jurkat cells to be most sensitive to argon plasma while THP-1 cells were most sensitive to He/O-2 plasma. Screening of 20 protein transcripts involved in redox regulation identified HMOX1 as a commonly regulated element, and siRNA-mediated knockdown of the HMOX1-transcribed protein HO-1 augmented plasma-derived cell death in the two leukemia cell lines. Interestingly, knockdown of the H2O2-decomposing enzyme catalase did not elevate plasma-induced cell death. By contrast, siRNA-mediated suppression of the production of the chemokine CXCL8 (IL8) markedly enhanced plasma-derived cytotoxicity up to twofold. Vice versa, by antibody-mediated blocking of IL8 receptors, a massive increase in IL8 and HO-1 secretion was observed, together with a dramatically enhanced cell death in response to plasma treatment, especially in THP-1 cells. These results suggest that the plasma-induced leukemia cell death is dictated by the ROS chemistry and the HO-1/CXCL8 axis via paracrine or autocrine IL8-mediated pro-survival signaling.