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Plasma Medicine
SJR: 0.278 SNIP: 0.183 CiteScore™: 0.57

ISSN Imprimir: 1947-5764
ISSN En Línea: 1947-5772

Plasma Medicine

DOI: 10.1615/PlasmaMed.2019029462
pages 57-88

Cold Atmospheric Plasma and Plasma-Activated Medium: Antitumor Cell Effects with Inherent Synergistic Potential

Georg Bauer
Institute of Virology, Medical Center and Faculty of Medicine, University of Freiburg, Hermann-Herder Str. 11, D-79104 Freiburg, Germany


Nitrite and H2O2, long-lived molecular species from cold atmospheric plasma (CAP) and plasma-activated medium (PAM), reach tumor target cells in vitro and in vivo. Through several steps, the interaction between nitrite and H2O2 leads to generation of singlet oxygen (1O2).1O2 then interacts with a specific biochemical switchboard on tumor cells that is composed of catalase, superoxide dismutase (SOD), first aptosis signal (FAS) receptor, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. As a result, local inactivation of catalase by minute concentrations of primary singlet oxygen opens a strong autoamplificatory sustained process of secondary singlet oxygen generation and catalase inactivation. This process is driven by tumor cell-specific NADPH oxidase-1 and spreads within the tumor cell population. The concerted action of singlet oxygen interaction with catalase, SOD, and FAS receptor causes an efficient mode of synergistic interaction. Defined reactive oxygen and reactive nitrogen species (ROS/RNS) such as H2O2 and nitrite have multiple functions in this process. Catalase-mediated oxidation of nitrite enhances generation of nitrogen dioxide, which is rate limiting for singlet oxygen generation. Before singlet oxygen-mediated inactivation of catalase and, subsequently, reactivated intercellular ROS/RNS signaling can activate the mitochondrial pathway of apoptosis, counteraction of glutathione to lipid peroxidation must be abrogated through aquaporin-mediated influx of H2O2 into cells. CAP- and PAM-dependent immunogenic cell death triggers a strong immune response that finalizes antitumor action in vivo. Thus, the high efficiency of CAP and PAM seem to depend on concerted action of several dominant steps and their autoamplificatory potential.


  1. Machala Z, Janda M, Hensel K, Jedlovsky I, Lestinska L, Foltin V, Martisovits V, Morvova M. Emission spectroscopy of atmospheric pressure plasmas for bio-medical and environmental applications. J Mol Spectroscopy. 2007;243:194-201.

  2. Stoffels E, Sakiyama Y, Graves DB. Cold atmospheric plasma: Charged species and their interactions with cells and tissues. IEEE Trans Plasma Sci. 2008;36:1441-57.

  3. Fridman G, Friedman G, Gutsol A, Shekhter AB, Vasilets VN, Fridman A. Applied plasma medicine. Plasma Proc Polym. 2008;5:503-33.

  4. Attri P, Arora B, Choi EH. Utility of plasma: A new road from physics to chemistry. RSC Adv. 2013;3:12540-67.

  5. Graves DB. The emerging role of reactive oxygen and nitrogen species in redox biology and some implications for plasma applications to medicine and biology. J Phys D Appl Phys. 2012;45:263001.

  6. Graves DB. Mechanisms of plasma medicine: Coupling plasma physics, biochemistry, and biology.IEEE Trans Radiat Plasma Med Sci. 2017;1:281-92.

  7. Laroussi M. Low-temperature plasma for medicine. IEEE Trans Plasma Sci. 2009;37:714-15.

  8. Laroussi M. From killing bacteria to destroying cancer cells: 20 years of plasma medicine. Plasma Proc Polym. 2014;11:1138-41.

  9. Laroussi M. Low-temperature plasmajet for biomedical applications: A review. IEEE Trans Plasma Sci. 2015;43:703-12.

  10. Laroussi M, Lu X, Keidar M. Perspective: The physics, diagnostics, and applications of atmospheric pressure low temperature plasma sources used in plasma medicine. J Appl Phys. 2017;122:020901.

  11. Lu X, Naidis GV, Laroussi M, Reuter S, Graves DB, Ostrikov K. Reactive species in non-equilibrium atmospheric-pressure plasmas: Generation, transport, and biological effects. Phys Rep Phys Lett. 2016;630:1-84.

  12. Graves DB. Reactive species from cold atmospheric plasma: Implications for cancer therapy. Plasma Proc Polym. 2014;11:1120-7.

  13. Graves DB. Oxy-nitroso shielding burst model of cold atmospheric plasma therapeutics. Clin Plasma Med. 2014;2:38-49.

  14. Jablonowski H, Bussiahn R, Hammer MU, Weltman K-D, von Woedtke T, Reuter S. Impact of plasma jet vacuum ultraviolet radiation on reactive species generation in bio-relevant liquids. Phys Plasmas. 2015;22:122008.

  15. Sousa JS, Niemi K, Cox LJ, Algwari QT, Gans T, O'Connell D. Cold atmospheric pressure plasma jets as sources of singlet delta oxygen for biomedical applications. J Appl Phys. 2011;109:123302.

  16. Machala Z, Tarabova B, Hensel K, Spetlikova E, Sikurova L, Lukes P. Formation of ROS and RNS in water electro-sprayed through transient spark discharge in air and their bactericidal effects. Plasma Proc Polym. 2013;10:649-59.

  17. Wende K, Williams P, Dalluge J, Van Gaens W, Akoubakr H, Bischof J, von Woedtke T, Goyal SM, Weltmann K-D, Bogaerts A, Masur K, Bruggeman PJ. Identification of biologically active liquid chemistry induced by nonthermal atmospheric pressure plasma jet. Biointerphases. 2015;10:029518.

  18. Schmidt-Bleker A, Bansemer R, Reuter S, Weltmann K-D. How to produce a NOx-instead of Ox-based chemistry with a cold atmospheric plasma jet. Plasma Proc Polym. 2016;13:1120-7.

  19. GianelaM, Reuter S,AguilaAL, Ritchie GAD, van Helden JPH. Detection of H02 in an atmospheric pressure plasma jet using optical feedback cavity-enhanced absorption spectroscopy. New J Phys. 2016;18:113027.

  20. Bauer G, Graves DB. Mechanisms of selective antitumor action of cold atmospheric plasma-derived reactive oxygen and nitrogen species. Plasma Proc Polym. 2016;13:1157-78.

  21. Bauer G. Signal amplification by tumor cells: Clue to the understanding of the antitumor effects of cold atmospheric plasma and plasma-activated medium. IEEE Trans Radiat Plasma Med Sci. 2018;2:87-98.

  22. Yan A, Talbot N, Nourmokammadi X, Cheng J, Canady J, Sherman JH, Keidar M. Principles of using cold atmospheric plasma stimulatedmedia for cancertreatment. Sci Rep. 2015;5:1833901-17.

  23. Kurake N, Tanaka H, Ishikawa K, Kondo T, Sekine M, Nakamura K, Kajiyama H, Kikkawa F, Mizuno M, Hori M. Cell survival of glioblastoma grown in medium containing hydrogen peroxide and/or nitrite, or in plasma-activated medium. Arch Biochem Biophys. 2016;605:102-8.

  24. Girard P-M, Arbabian A, Fleury M, Bauville G, PuechV, Dutreix M, Sousa JS. Synergistic effect of H2O2 and NO" in cell death induced by cold atmospheric He plasma. Sci Rep. 2016;6:29098.

  25. Uchida G, Nakajima A, Takenaka K, Kawasaki T, Koja K, Shiratani M, Setsuhara Y. Effects ofnon-thermal plasma jet irradiation on the selective production of H2O2 and NO" in liquid water. J Appl Phys. 2016;120:201102.

  26. Dobrynin D, Fridman G, Friedman G, Fridman A. Physical and biological mechanisms of direct plasma interaction with living tissue. New J Phys. 2009;11:115020.

  27. Vandamme M, Pesnel S, Barbosa E, Dozias S, Sobilo J, Lerondel S, Le Pape A, Pouvesle J-M. Antitumor effect of plasma treatment on U87 glioma xenografts: Preliminary results. Plasma Proc Polym. 2010;7:264-73.

  28. Von Woedtke T, Metelmann H-R, Weltmann K-D. Clinical plasma medicine: State and perspectives of in vivo application of cold atmospheric plasma. Contrib Plasma Phys. 2014;54:104-17.

  29. Keidar M. Plasma for cancer treatment. Plasma Sources Sci Technol. 2015;24:033001.

  30. Yan DY, Sherman JH, Keidar M. Cold atmospheric plasma, a novel promising anti-cancer treatment modality. Oncotarget. 2017;8:15977-95.

  31. Metelmann H-R, Nedrelow DS, Seebauer C, Schuster M, von Woedtke T, Weltmann K-D, Kindler S, Metelmann PH, Finkelstein SE, Von Hoff DD. Head and neck cancer treatment and physical plasma. Clin Plasma Med. 2015;3:17-23.

  32. Metelmann H-R, Seebauer C, Miller V, Fridman A, Bauer G, Graves DB, Pouvesle J-M, Rutkowski R, Schuster M, Bekeschus S, Wende K, Masur K, Hasse S, Gerling T, Hori M, Tanaka H, Choi EH, Weltmann K-D, Metelmann PH, von Hoff DD, von Woedtke T. Clinical experience with cold plasma in the treatment of locally advanced head and neck cancer. Clin Plasma Med. 2018;9:6-13.

  33. Metelmann HR, Seebauer C, Rutkowski R, Schuster M, Bekeschus S, Metelmann P. Treating cancer with cold physical plasma: On the way to evidence-based medicine. Contrib Plasma Phys. 2018;58:415-9.

  34. Schuster M, Seebauer C, Rutkowski R, Hauschild A, Podmelle F, Metelmann C, Metelmann B, Von Woedtke T, Hasse S, Weltmann K-D, Metelmann H-R. Visible tumor surface response to physical plasma and apoptotic cell kill in head and neck cancer. J Craniomaxillofac Surg. 2016;44:1445-52.

  35. Weltmann KD, von Woedtke T. Plasma medicine-Current state of research and medical application. Plasma Phys Contr Fusion. 2017;59(1):014.

  36. Machala Z, Chladekova L, Pelach M. Plasma agents in bio-decontamination by DC discharges in atmospheric air. J Phys D Appl Phys. 2010;43:222001.

  37. Wu H, Sun P, Feng H, Zhou H, Wang R, Liang Y, Lu J, Zhu W, Zhang J, Fang J. Reactive oxygen species in a nonthermal plasma microjet and water system: Generation, conversion and contributions to bacteria inactivation-An analysis by electron spin resonance spectroscopy. Plasma Proc Polym. 2012;9:417-24.

  38. Traylor MJ, Pavlovich MJ, Karim S, Hait P, Sakiyama Y, Clark DS, Graves DB. Long-term antibacte-rialefficacy ofairplasma-activatedwater. JPhysD ApplPhys. 2011;44:472001.

  39. Aboubakr A, Gangal U, Youssef MM, Goyal SM, Bruggeman PJ. Inactivation of virus in solution by cold atmospheric pressure plasma: Identification of chemical inactivation pathways. J Phys D Appl Phys. 2016;48:204001.

  40. Isbary G, Morfill G, Schmidt HU, Georgi M, Ramrath K, Heinlein J, Karrer S, Landthaler M, Shimizu T, Steffes B, Bunk W, Monetti R, Zimmermann JL, Pompl R, Stolz W. A first prospective randomized controlled trial to decrease bacterial load using cold atmospheric argon plasma on chronic wounds in patients. Br J Dermatol. 2010;163:78-82.

  41. Arndt S, Unger P, Wacker E, Shimizu T, Heinlin J, Li J-F, Thomas HM, Morfill GE, Zimmermann JL, Bosserhoff A-K, Karrer S. Cold atmospheric plasma (CAP) changes gene expression of key molecules of the wound healing machinery and improves wound healing in vitro and in vivo. PLOS ONE. 2013;8:e79325.

  42. Hasse S, Tran D, Hahn O, Kindler S, Metelmann H-R, von Woedtke T, Masur K. Induction of proliferation of basal epidermal keratinocytes by cold atmospheric-pressure plasma. Clin Exp Dermatol. 2016;41:202-9.

  43. Schmidt A, Bekeschus S, Wende K, Vollmar B, von Woedtke T. A cold plasma jet accelerates wound healing inamurine model offull-thickness skinwounds. Exp Dermatol. 2017;26:156-62.

  44. Heinlin J, Isbary G, Stolz W, Morfill G, Landthaler M, Shimizu T, Steffes B, Nosenko T, Zimmermann JL, Karrer S. Plasma applications in medicine with a special focus on dermatology. J Eur Acad Dermatol Venereol. 2011;25(1):1-11.

  45. Friedman PC, Miller V, Fridman G, Lin A, Fridman A. Successful treatment of actinic keratosis using nonthermal atmospheric pressure plasma: A case series. J Am Acad Dermatol. 2017;76: 340-50.

  46. Wirtz M, Stoffels I, Dissemond J, Schadendorf D, Roesch A. Actinic keratoses treated with cold atmospheric plasma. J Eur Acad Dermatol Venereol. 2018;32:e37-9.

  47. Keidar M, Walk R, Shashurin A, Srinivasan P, Sandler P, Sandler A, Dasgupta S, Ravi R, Guerrero-Preston R, Trink B. Cold plasma selectivity and the possibility of a paradigm shift in cancer therapy. Br J Cancer. 2011;105:1295-301.

  48. Keidar M, Shashurin A, Volotskova O, Stepp MA, Srinivasan P, Sandler A, Trink B. Cold atmospheric plasma in cancer therapy. Phys Plasma. 2013;20:057101.

  49. Ishaq M, Evans M, Ostrikov K. Effect of atmospheric gas plasmas on cancer cell signaling. Int J Cancer. 2013;134:1517-28.

  50. Barekzi N, Laroussi M. Effects of low temperature plasmas on cancer cells. Plasma Proc Polym. 2013;10:1039-50.

  51. SchlegelJ,KoritzerJ,Boxhammer V. Plasmaincancertreatment. ClinPlasmaMed. 2013;1:2-7.

  52. Tanaka H, Mizuno M, Ishikawa K, Takeda K, Nakamura K, Utsumi F, Kajiyama H, Kano H, Okazaki Y, Toyokuni S, Maruyama S, Kikkawa F, Hori M. Plasma medical science for cancer therapy: Toward cancer therapy using nonthermal atmospheric pressure plasma. IEEE Trans Plasma Sci. 2013;42:3760-4.

  53. Ratovitski EA, Heng X, Yan D, Sherman JH, Canady J, Trink B, Keidar M. Anti-cancer therapies of the 21st century: Novel approach to treat human cancers using cold atmospheric plasma. Plasma Proc Polym. 2014;11:1128-37.

  54. Babington P, Rajjoub K, Canady J, Siu A, Keidar M, Sherman JH. Use of cold atmospheric plasma in the treatment of cancer. Biointerphases. 2015;10:029403.

  55. Gay-Mimbrera J, Garcia MC, Tejera BI, Rodero-Serrano A, Garcia-Nieto AV, Ruano J. Clinical and biological principles of cold atmospheric plasma application in skin cancer. Adv Ther. 2016;33:894-909.

  56. Bauer G, Graves DB, Schuster M, Metelmann H-R. Side effect management. In: Metelmann H-R, von Woedtke T, Weltmann K-D, editors. Comprehensive clinical plasma medicine. Berlin: Springer; 2pp. 301-18.

  57. Kalghati S, Kelly C, Cerchar E, Azizkhan-Clifford J. Selectivity of non-thermal atmospheric-pressure microsecond-pulsed dielectric barrier discharge plasma induced apoptosis in tumor cells over healthy cells. Plasma Med. 2011;1:249-63.

  58. Tanaka H, Ishikawa K, Nakamura K, Kajiyama H, Komo H, Kikkawa T, Hori M. Plasma-activated medium selectively kills glioblastoma brain tumor cells by down-regulating a survival signaling molecule, AKT kinase. Plasma Med. 2011;1:265-77.

  59. Zucker SN, Zirnheld J, Bagati A, DiSanto TM, Des Soye B, Wawrzyniak JA, Eternadi K, Nikiforov M, Berezney R. Preferential induction of apoptotic cell death in melanoma cells as compared with normal keratinocytes using a non-thermal plasma torch. Cancer Biol Ther. 2012;13:1299-306.

  60. Wang M, Holmes B, Cheng X, Zhu W, Keidar M, Zhang LG. Cold atmospheric plasma for selectively ablating metastatic breast cancer cells. PLOS ONE. 2013;8:e73741.

  61. Guerrero-Preston R, Ogawa T, Uemura M, Shumulinsky G, Valle BL, Pirini F, Ravi R, Sidransky D, Keidar M, Trink B. Cold atmospheric plasma treatment selectively targets head and neck squamous cell carcinoma cells. Int J Mol Med. 2014;34:941-6.

  62. Kaushik N, Kumar N, Kim CH, Kaushik N, Choi EH. Dielectric barrier discharge plasma efficiently delivers an apoptotic response in human monocytic lymphoma. Plasma Proc Polym. 2014;11:1175-87.

  63. Utsumi F, Kajiyama H, Nakamura K, Tanaka H, Hori M, Kikkawa F. Selective cytotoxicity of indirect nonequilibrium atmospheric pressure plasma against ovarian clear-cell carcinoma. Springerplus. 2014;3:398.

  64. Siu A, Volotskova O, Cheng X, Khaisa SS, Bian K, Murad F, Keidar M, Sherman JH. Differential effects of cold atmospheric plasma in the treatment of malignant glioma. PLOS ONE. 2015;10:e0126313.

  65. Kim SJ, Chung TH. Cold atmospheric plasma jet-generated RONS and their selective effects on normal and carcinoma cells. Sci Rep. 2016;6:20332.

  66. Duan J, Lu X, He G. The selective effect of plasma-activated medium in an in vitro co-culture of liver cancer and normal cells. J Appl Phys. 2017;121:013302.

  67. Canal C, Fontelo R, Hamouda I, Guillem-Marti J, Cvelbar U, Ginebra M-P. Plasma-induced selectivity in bone cancer cell death. Free Radic Biol Med. 2017;110:72-80.

  68. Liedke KR, Bekeschus S, Kaeding A, Hackbarth C, Kuehn JP, Heidecke CD, von Bernstorff W, von Woedtke T, Partecke LI. Non-thermal plasma-treated solution demonstrates antitumor activity against pancreatic cancer cells in vitro and in vivo. Sci Rep. 2017;7:8319.

  69. Wende K, StraBenburg S, Haertel B, Harms M, Holtz S, Barton A, Masur K, von Woedtke T, Lindequist U. Atmospheric pressure plasma jet treatment evokes transient oxidative stress in HaCaT keratinocytes and influences cell physiology. Cell Biol Int. 2014;38:412-25.

  70. Hirst AM, Simms MS, Mann VM, Maitland NJ, O'Connell D, Frame FM. Low temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells. Br J Cancer. 2015;112:1536-45.

  71. Bekeschus S, Masur K, Kolata J, Wende K, Schmidt A, Bundscherer L, Barton A, Kramer A, Broker B, Weltmann K-D. Human mononuclear cell survival and proliferation is modulated by cold atmospheric plasma jet. Plasma Proc Polym. 2013;10:706-13.

  72. Bekeschus S, Iseni S, Reuter S, Masur K, Weltmann K-D. Nitrogen shielding ofan argon plasmajet and its effects on human immune cells. IEEE Trans Plasma Sci. 2015;43:776-81.

  73. Bundscherer L, Bekeschus S, Tresp H, Hasse S, Reuter S, Weltmann K-D, Lindequist U, Masur K. Viability of human blood leucocytes compared with their respective cell lines after plasma treatment. Plasma Med. 2013;3:71-80.

  74. Vandamme M, Robert E, Lerondel S, Sarron V, Ries D, Dozias S, Sobilo J, Gosset D, Kieda C, Legrain B, Pouvesle J-M, Le Pape A. ROS implication in a new antitumor strategy based on nonthermal plasma. Int J Cancer. 2012;130:2185-94.

  75. Bauer G. Increasing the endogenous NO level causes catalase inactivation and reactivation of inter-cellularapoptosis signaling specifically intumor cells. RedoxBiol. 2015;6:353-71.

  76. Bauer G. The antitumor effectofsinglet oxygen. AnticancerRes. 2016;36:5649-64.

  77. Garg AD, Agostinos P. ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. Photochem Photobiol Sci. 2014;13:474-87.

  78. Lin A, Truong B, Pappas A, Kirifides L, Oubarri A, Chen S, Lin S, Dobrynin D, Fridman G, Fridman A, Sang N, Miller V. Uniform nanosecond pulsed dielectric barrier discharge plasma enhances anti-tumor effects by induction of immunogenic cell death in tumors and stimulation of macrophages. Plasma Proc Polym. 2015;12:1392-9.

  79. Lin A, Truong B, Patel S, Kaushik N, Choi EH, Fridman G, Fridman A, Miller V. Nanosecond-pulsed DBD plasma-generated reactive oxygen species trigger immunogenic cell death in A549 lung carcinoma cells through intracellular oxidative stress. Int J Mol Sci. 2017;18:966.

  80. Lin A, Truong B, Fridman G, Fridman A, Miller V. Immune cells enhance selectivity of nanosecond-pulsed DBD plasma against tumor cells. Plasma Med. 2017;7:85-96.

  81. Lin AG, Xiang B, Merlino DJ, Baybutt TR, Sahu J, Fridman A, Snook AE, Miller V. Non-thermal plasma induces immunogenic cell death in vivo in murine CT26 colorectal tumors. Oncoimmunology. 2018;7:e148978.

  82. Miller V, Lin A, Fridman A. Why target immune cells for plasma treatment of cancer? Plasma Chem Plasma Proc. 2016;36:259-68.

  83. Mizuno K, Yonetamari Y, Shirakawa Y, Akiyama T, Ono R. Anti-tumor immune response induced by nanosecond pulsed streamer discharge in mice. J Phys D Appl Phys. 2017;50:12LT01.

  84. Bekeschus S, Mueller A, Miller V, Gaipl U, Weltmann K-D. Physical plasma elicits immunogenic cancer cell death and mitochondrial singlet oxygen. IEEE Trans Rad Plasma Med Sci. 2018;2(2): 138-46.

  85. Bekeschus S, Clemen R, Metelmann H-R. Potentiating anti-tumor immunity with physical plasma. Clin Plasma Med. 2018;12:17-22.

  86. Kaushik NK, Kaushik N, Min B, K. Choi KH, Hong YJ, Miller V, Fridman A, Choi EH. Cytotoxic macrophage-released tumour necrosis factor-a (TNF-a) as a killing mechanism for cancer cell death after cold plasma activation. J Phys D Appl Phys. 2018;49:084001.

  87. Apetoh L, Tesnier A, Ghiringhelli F, Kroemer G, Zitvogel L. Interactions between dying tumor cells and the innate immune system determine the efficiency of conventional antitumor therapy. Cancer Res. 2008;68:4026-30.

  88. Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353-63.

  89. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012;12:860-75.

  90. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Ann Rev Immunol. 2013;31:51-72.

  91. Candeias SM, Gaipl US. The immune system in cancer prevention, development and therapy. Anticancer Agents Med Chem. 2016;16:101-7.

  92. Utsumi F, Kajiyama H, Nakamura K, Tanaka H, Mizuno M, Ishikawa K, Kondo H, Kano H, Hori M, Kikkawa F. Effect of indirect nonequilibrium atmospheric pressure plasma on anti-proliferative activity against chronic chemoresistant ovarian cancer cells in vitro and in vivo. PLOS ONE. 2013;8:e81576.

  93. Yan D, Sherman JH, Cheng X, Ratovitski E, Canady J, Keidar M. Controlling plasma stimulated media in cancer treatment application. Appl Phys Lett. 2014;105:22410101-4.

  94. Adachi T, Tanaka H, Nonomura S, Hara H, Kondo S-I, Hori M. Plasma-activated medium induces A459 cell injury via a spiral apoptotic cascade involving the mitochondrial-nuclear network. Free Radic Biol Med. 2015;79:28-44.

  95. Mohades S, Laroussi M, Sears J, Barekzi N, Razavi H. Evaluation of the effects of a plasma-activated medium on cancer cells. Phys Plasmas. 2015;22:122001.

  96. Kumar N, Park JH, Jeon SN, Park BS, Chori EH, Attri P. The action of microsecond-pulsed plasma-activated media on the inactivation of human lung cancer cells. J Phys D Appl Phys. 2016;49:11540101-9.

  97. Yan D, Nourmohammadi N, Bian K, Murad F, Sherman JH, Keidar M. Stabilizing the cold plasma-stimulated medium by regulating medium's composition. Sci Rep. 2016;6:2602.

  98. Koensgen D, Besic I, Gumbel D, Kaul A, Weiss M, Diesing K, Kramer A, Bekeschus S, Mustea A, Stope MB. Cold atmospheric plasma (CAP) and CAP-stimulated cell culture media suppress ovarian cancer cell growth-A putative treatment option in ovarian cancer therapy. Anticancer Res. 2017;37:6739-44.

  99. Szili EJ, Bradley JW, Short RD. A "tissue model" to study the plasma delivery of reactive oxygen species. J Phys D Appl Phys. 2014;47:152002.

  100. Szili EJ, Oh JS,Hong SH,HattaA, ShortRD. Probing the transport of plasma-generated RONS in an agarose target as surrogate for real tissue: Dependency on time, distance and material composition. J Phys D Appl Phys. 2015;48:202001.

  101. Szili EJ, Hong S-H, Oh J-S, Gaur N, Short RD. Tracking the penetration of plasma reactive species in tissue models. Trends Biotechnol. 2018;36:594-602.

  102. Szili EJ, Oh JS, Fukuhara H, Bhatia R, Gaur N, Nguyen CK, Hong SH, Ito S, Ogawa K, Kawada C, Shuin T, Tsuda M, Furikata M, Kurabayashi A, Furuta H, Ito M, Inoue K, Hatta A, Short RD. Modelling the helium plasma jet delivery of reactive species into a 3D cancer tumor. Plasma Sources Technol. 2018;27:014001.

  103. Nie L, Yang Y, Duan J, Sun F, Lu X, He G. Effect of tissue thickness and liquid composition on the penetration of long-lifetime reactive oxygen and nitrogen species (RONS) generated by plasma jet. J Phys D Appl Phys. 2018;51:345204.

  104. Ivanovas B, Bauer G. Selective and nonselective apoptosis induction in transformed and nontransformed fibroblasts by exogenous reactive oxygen and nitrogen species. Anticancer Res. 2002;22: 841-56.

  105. Bohm B, Heinzelmann S, Motz M, Bauer G. Extracellular localization ofcatalase is associated with the transformed state of malignant cells. Biol Chem. 2015;396:1339-56.

  106. Bechtel W, Bauer G. Catalase protects tumor cells against apoptosis induction by intercellular ROS signaling. Anticancer Res. 2009;29:4541-57.

  107. Bechtel W, Bauer G. Modulation of intercellular ROS signaling of human tumor cells. Anticancer Res. 2009;29:4559-70.

  108. Heinzelmann S, Bauer G. Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling ofhuman tumor cells. Biol Chem. 2010;391:675-93.

  109. Bauer G, Zarkovic N. Revealing mechanisms of selective, concentration-dependent potentials of 4-hydroxy-2-nonenal to induce apoptosis in cancer cells through inactivation of membrane-associated catalase. Free Radic Biol Med. 2015;81:128-44.

  110. Bauer G, Motz M. The antitumor effect of single-domain antibodies directed towards membrane-associated catalase and superoxide dismutase. Anticancer Res. 2016;36:5945-56.

  111. Bauer G. Tumor cell protective catalase as a novel target for rational therapeutic approaches based on specific intercellular ROS signaling. Anticancer Res. 2012;32:2599-24.

  112. BauerG. Targeting extracellularROS signaling oftumorcells. AnticancerRes. 2014;34:1467-82.

  113. Bauer G. SiRNA-based analysis of the abrogation of the protective function of membrane-associated catalase oftumor cells. Anticancer Res. 2017;37:567-82.

  114. Bauer G. Targeting the protective catalase of tumor cells with cold atmospheric plasma-treated medium (PAM). Anticancer Agents Med Chem. 2018;18:784-804.

  115. Riethmuller M, Burger N, Bauer G. Singlet oxygen treatment oftumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling. Redox Biol. 2015;6:157-68.

  116. Scheit K, Bauer G. Direct and indirect inactivation of tumor cell protective catalase by salicylic acid and anthocyanidins reactivates intercellular ROS signaling and allows for synergistic effects. Carcinogenesis. 2015;36:400-11.

  117. Bauer G. Autoamplificatory singlet oxygen generation sensitizes tumor cells for intercellular apoptosis-inducing signaling. Mech Ageing Dev. 2018;172:59-77.

  118. Yan DY, Talbot A, Nourmohammadi N, Sherman JH, Cheng XQ, Keidar M. Toward understanding the selective anticancer capacity of cold atmospheric plasma-A model based on aquaporins. Biointerphases. 2015;10:040801.

  119. Yan D, Xiao H, Zhu W, Nourmohammadi N, Zhang LG, Bian K, Keidar M. The role of aquaporins in the anti-glioblastoma capacity of the cold plasma-stimulated medium. J Phys D Appl Phys. 2017;50:055401.

  120. Irani Y, Xia J, Zweier L, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-ClermontPJ. Mtogenic signalling by oxidants in Ras-transformed fibroblasts. Science. 1997;275:1649-52.

  121. Herdener M, Heigold S, Saran M, Bauer G. Target cell-derived superoxide anions cause efficiency and selectivity of intercellular induction of apoptosis. Free Radic Biol Med. 2000;29:1260-71.

  122. Heigold S, Sers C, Bechtel W, Ivanovas B, Schafer R, Bauer G. Nitric oxide mediates apoptosis induction selectively in transformed fibroblasts compared to nontransformed fibroblasts. Carcino-genesis. 2002;23:929-41.

  123. Bauer G. Nitric oxide contributes to selective apoptosis induction in malignant cells through multiple reaction steps. CritRev Oncogen. 2016;21:365-98.

  124. Bauer G. HOCl and the control of oncogenesis. J Inorgan Biochem. 2018;179:10-23.

  125. Kono Y, Fridovich I. Superoxide radical inhibits catalase. J Biol Chem. 1982;257:5751-4.

  126. Shimizu N, Kobayashi K, Hayashi K. The reaction of superoxide radical with catalase. Mechanism of the inhibition of catalase by superoxide radical. J Biol Chem. 1984;259:4414-18.

  127. Gebicka L, Metodiewa D, Gebicki JL. Pulse radiolysis of catalase in solution. I. Reactions of 02 with catalase and its compound. Int J Rad Biol. 1989;55:45-50.

  128. Lardinois OM. Reactions of bovine liver catalase with superoxide radicals and hydrogen peroxide. FreeRadRes. 1995;22:251-74.

  129. Bauer G. HOCl-dependent singlet oxygen and hydroxyl radical generation modulate and induce apoptosis ofmalignant cells. AnticancerRes. 2013;33:3589-602.

  130. Escobar JA, Rubio A, Lissi EA. SOD and catalase inactivation by singlet oxygen and peroxyl radicals. Free Rad Biol Med. 1996;20:285-90.

  131. Kim YK, Kwon OJ, Park J-W. Inactivation of catalase and superoxide dismutase by singlet oxygen derived from photoactivated dye. Biochimie. 2001;83:437-44.

  132. Jablonowski H, von Woedtke T. Research on plasma medicine-relevant plasma-iquid interaction: Whathappenedinthe pastfive years? Clin PlasmaMed. 2015;3:42-52.

  133. Whiteside C, Hassan HM. Role of oxyradicals in the inactivation of catalase by ozone. Free Rad Biol Med. 1988;5:305-12.

  134. Lee Y-K, Kim SMK, Hand S. Ozone-induced inactivation of antioxidant enzymes. Biochimie. 2003; 85:947-52.

  135. Zhuang S, Demir JT, Kochevar IE. Protein kinase C inhibits singlet oxygen-induced apoptosis by decreasing caspase-8 activation. Oncogene. 2001;20:6764-76.

  136. Suzuki Y, Ono Y, Hirabayashi Y. Rapid and specific reactive oxygen species generation via NADPH oxidase activation during FAS-mediated apoptosis. FEBS Lett. 1998;425:209-12.

  137. Reinehr S, Becker S, Eberle A, Grether-Beck S, Haussinger D. Involvement of NADPH oxidase isoforms and SRC family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem. 2005; 280:27179-94.

  138. Selleri C, Sato T, Raiola AM, Rotoli B, Young NS, Maciejewski JP. Induction of nitric oxide synthase is involved in the mechanism of FAS-mediated apoptosis in hematopoietic cells. Br J Hematol. 1997;99:481-9.

  139. Krych-Madej, J, Gebicka L. Interactions of nitrite with catalase: Enzyme activity and reaction kinetic studies. J Inorg Biochem. 2017;17:10-7.

  140. Imai H, Nakagawa Y. Biological significance ofphospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med. 2003;34:145-69.

  141. Bauer G. Central signaling elements of intercellular reactive oxygen/nitrogen species-dependent induction ofapoptosis in malignant cells. Anticancer Res. 2017;37:499-514.

  142. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: An update and review. Biochem Biophys Acta. 2006;1757:509-17.

  143. Pletjushkina OY, Fetisova EK, Lyamzaev KG, Ivanova OY, Domnina LV, Vysskikh MY, Pustovidko AV, Vasiliev JM, Murphy MP, Chernyak BV, Skulachev VP. Long-distance apoptotic killing of cells is mediated by hydrogen peroxide in a mitochondrial ROS-dependent fashion. Cell Death Differen. 2005;12:1442-4.

  144. Chiang CLL, Ledermann JA, Rad AN, Katz DR, Chain BM. Hypochlorous acid enhances immuno-genicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells. Cancer Immunol Immunother. 2006;55:1384-95.

  145. Chiang CLL, Ledermann JA, Aitkens E, Benjamin E, Katz DR, Chain BM. Oxidation of ovarian epithelial cancer cells by hypochlorous acid enhances immunogenicity and stimulates T cells that recognize autologous primary tumor. Clin Cancer Res. 2008;14:4898-907.

  146. Chiang CLL, Coukos G, Kandalaft LE. Whole tumor antigen vaccines: Where are we? Vaccines. 2015;3:344-72.

  147. Prokopowicz ZM, Arce F, Biedron R, Chiang CLL, Ciszek M, Katz DR, Nowakowska M, Zapotoczny S, Marcinkiewicz J, Chain BM. Hypochlorous acid: A natural adjuvant that facilitates antigen processing, cross-priming, and the induction of adaptive immunity. J Immunol. 2010;184:824-35.

  148. Biedron R, Konopinski K, Marcinkiewicz J, Jozefowski S. Oxidation by neutrophil-derived HOC1 increases immunogenicity of proteins by converting them into ligands of several endocytic receptors involved in antigen uptake by dendritic cells and macrophages. PLOS ONE. 2015;10:e01123293.

  149. Zhou R, Huang W-L, Ma C, Zhou Y, Yao Y-Q, Wang Y-X, Gou L-T, Chen Y, Yang J-L. HOC1 oxidation-modified CT26 cell vaccine inhibits colon tumor growth in a mouse model. Asian Pacific J Cancer Preven. 2012;13:4037-43.

  150. Held AM, Halko DJ, Hurst JK. Mechanisms of chlorine oxidation of hydrogen peroxide. J Am Chem Soc. 1978;100:5732-40.

  151. Miyamoto S, Martinez GR, Rettori D, Augusta O, Medeiros MHG, Di Mascio P. Linoleic acid hydroperoxide reacts with hypochlorous acid, generating peroxyl radical intermediates and singlet molecular oxygen. Proc Natl Acad Sci USA. 2006;103:293-8.

  152. Miyamoto S, Ronsein GE, Prado FM, Uemi M, Correa TC, Toma IN, Bertolucci A, Oliviera MCB, Motta FD, Medeiros MHG, Di Mascio P. Biological hydroperoxides and singlet molecular oxygen generation. IUMB Life. 2007;59:322-31.

  153. Sies H. Role of metabolic H2OGeneration, redox signaling and oxidative stress. J Biol Chem. 2014; 289:8735-41.

  154. Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol. 2017;11:613-9.