br Immunohistochemical staining revealed the
Immunohistochemical staining revealed the abolished vimentin levels and increased E-cadherin levels in the tissues subjected to dual treat-ment. Overall, H2O2 was generated in CAP-treated A549 cancer U 46619 [59,60], while Fe2+/Fe3+ from iron oxide-based MNPs can transform H2O2 into •OH via Fenton’s reaction . Iron oxide-based MNPs can enhance the tumor-killing eﬀect of CAP through this mechanism (Fig. 10). These results suggested that dual treatment with CAPs and iron oxide-based MNPs potentially inhibited tumor growth.
In summary, the eﬀect of co-treatment of CAP and iron oxide-based MNPs both in vitro and in vivo has been demonstrated. The co-treat-ment could eﬀectively induce A549 cancer cells apoptosis in vitro via the inhibition of EGFR-RAS/ERK and EGFR-PI3K/AKT signaling path-ways and the modulation of EMT. The co-treatment also suppressed xenograft tumor growth. Thus, the combination of CAP and iron oxide-based MNPs may lead to a shift in the paradigm of cancer therapy.
This work was supported by a grant from the National Natural Science Foundation of China, China (81774125) and The Natural Science Foundation of Shandong Province, China (ZR2015HL064). The work at George Washington University was supported in part by National Science Foundation, USA (1465061).
WL, ZC, MK, WZ: conception and design, data analysis and inter-pretation, and manuscript writing and revision; WL, ZC, HY, DD, YW, SW, XL: conduct experiments and data analysis. All authors have given approval to the final version of the manuscript
Conflict of interest
The authors declare no conflict of interest.
M. Keidar, Adaptation of operational parameters of cold atmospheric plasma for in vitro treatment of cancer cells, ACS Appl. Mater. Interfaces 10 (2018) 9269–9279.  Z. Chen, L. Lin, Q. Zheng, J.H. Sherman, J. Canady, B. Trink, M. Keidar, Micro-sized cold atmospheric plasma source for brain and breast cancer treatment, Plasma Med. Free Radical Biology and Medicine 130 (2019) 71–81
Fig. 10. Molecular mechanisms of MNPs enhancing tumor-selective killing eﬀect of CAP. CAP-originated reactive species will cause a noticeable rise of in-tracellular H2O2, Fe2+/Fe3+ released from the lyso-some containing MNPs could catalyzed H2O2 into OH., which cause the injury of cancer cells, such as inducing mitochondria-mediated apoptosis and double strand DNA breaks.
M. Balasubramanian, V.N. Vasilets, A.F. Gutsol, A. Fridman, G. Friedman, Mechanism of blood coagulation by nonthermal atmospheric pressure dielectric barrier discharge plasma, IEEE Trans. Plasma Sci. 35 (5) (2007) 1559–1566.
 N. Kumar, P. Attri, D.K. Yadav, J. Choi, E.H. Choi, H.S. Uhm, Induced apoptosis in melanocytes cancer cell and oxidation in biomolecules through deuterium oxide generated from atmospheric pressure non-thermal plasma jet, Sci. Rep. 4 (2014) 7589.
 V.S.K. Kondeti, C.Q. Phan, K. Wende, H. Jablonowski, U. Gangal, J.L. Granick, R.C. Hunter, P.J. Bruggeman, Long-lived and short-lived reactive species produced by a cold atmospheric pressure plasma jet for the inactivation of Pseudomonas aeruginosa and Staphylococcus aureus, Free Radic. Biol. Med. 124 (2018) 275–287.
J. Zimmermann, Plasma medicine: an introductory review, New J. Phys. 11 (11)
J.S. Pajarinen, H. Nejadnik, S. Goodman, M. Moseley, Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues, Nat. Nanotechnol. 11 (11) (2016) 986.
 X. Fang, X. Cheng, Y. Zhang, L.G. Zhang, M. Keidar, Single-step synthesis of carbon encapsulated magnetic nanoparticles in arc plasma and potential biomedical ap-plications, J. Colloid Interface Sci. 509 (2018) 414–421.
P. Descargues, S. Arbault, O. Burlet-Schiltz, L. Casteilla, Mechanistic insights into the impact of cold atmospheric pressure plasma on human epithelial cell lines, Sci. Rep. 7 (2017) 41163.