Side Effect Management

  • Georg Bauer
  • David B. Graves
  • Matthias Schuster
  • Hans-Robert Metelmann


Side effect management of CAP-based medical applications requires detailed knowledge about (1) reactive oxygen and nitrogen species (ROS/RNS) in CAP and in CAP-treated fluids, (2) potential interactions of these ROS/RNS, (3) their target structures in nonmalignant and malignant cells, or in microbes, (4) the site of their action in biological systems and (5) the extent of antioxidative counteraction of living cells towards CAP, (6) the impact of ROS/RNS on inter- and intracellular signaling systems and (7) the borderline between signaling and damaging effects of CAP-derived ROS/RNS. The available literature and further studies should allow to define the dose ranges of CAP that cause a beneficial antitumor or antimicrobial effect without detrimental side effects. The rigid analysis of the very few reports on detrimental or nonselective effects of CAP might allow to define the limits of application, whereas the analysis of specific and beneficial CAP effects should be instrumental for further optimization of medical application of CAP. This chapter also points to specific responses of targeted microbes and tumor cells that amplify the initial CAP-mediated signal. They thus allow the use of non-damaging doses of CAP and establishment of a site-specific strong response in defined target structures.


Cold atmospheric plasma Reactive oxygen species Reactive nitrogen species Glutathione Mutagenicity Apoptosis Antimicrobial treatment Tumor treatment Selectivity 


  1. 1.
    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.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Von Woedtke T, Metelmann H-R, Weltmann KD. Clinical plasma medicine: state and perspectives of in vivo application of cold atmospheric plasma. Contrib Plasma Phys. 2014;54:104–17.CrossRefGoogle Scholar
  3. 3.
    Lademann J, Richter H, Alborov A, Hume D, Patzelt A, Kramer A, Weltmann K-D, Hartmann B, Ottomann C, Fluhr JW, Hinz P, Hübner G, Lademann O. Risk assessment of the application of a plasma jet in dermatology. J Biomed Opt. 2009;14:054025. Scholar
  4. 4.
    Sies H. Strategies of antioxidant defense. FEBS J. 1993;215:213–9. Scholar
  5. 5.
    Sies H. Role of metabolic H2O2. Generation, redox signaling and oxidative stress. J Biol Chem. 2014;289:8735–41.CrossRefGoogle Scholar
  6. 6.
    Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol. 2017;11:613–8.CrossRefGoogle Scholar
  7. 7.
    Bauer G, Chatgilialoglu C, Gebicki JL, Gebicka L, Gescheidt G, Golding BT, Goldstein S, Kaizer J, Merenyi G, Speier G, Wardman P. Biologically relevant small radicals. Chimia. 2008;62:1–9.CrossRefGoogle Scholar
  8. 8.
    Bauer G. Helicobacter and reactive oxygen species. In: Gracia-Sancho J, Salvadó J, editors. Gastrointestinal tissue. Oxidative stress and dietary antioxidants. Cambridge: Academic; 2017. p. 81–96.Google Scholar
  9. 9.
    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(26):263001.CrossRefGoogle Scholar
  10. 10.
    Graves DB. Reactive species from cold atmospheric plasma: implications for cancer therapy. Plasma Process Polym. 2014;11:1120–7.CrossRefGoogle Scholar
  11. 11.
    Graves DB. Oxy-nitroso shielding burst model of cold atmospheric plasma therapeutics. Clin Plasma Med. 2014;2:38–49.CrossRefGoogle Scholar
  12. 12.
    Jablonowski H, Bussiahn R, Hammer MU, Weltman DK, 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.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    Schmidt-Bleker A, Bansemer R, Reuter S, Weltmann K-D. How to produce an NOx-indstead of Ox-based chemistry with a cold atmospheric plasma jet. Plasma Process Polym. 2016.
  15. 15.
    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. Scholar
  16. 16.
    Gianella M, Reuter S, Aguila AL, Ritchie GAD, van Helden JPH. Detection of HO2 in an atmospheric pressure plasma jet using optical feedback cavity-enhanced absorption spectroscopy. New J Phys. 2016;18:113027.CrossRefGoogle Scholar
  17. 17.
    Bauer G, Graves DB. Mechanisms of selective antitumor action of cold atmospheric plasma-derived reactive oxygen and nitrogen species. Plasma Process Polym. 2016;13:1157–78.CrossRefGoogle Scholar
  18. 18.
    Lackmann J-W, Baldus S, Steinborn E, Edengeiser E, Kogelheide F, Langklotz S, Schneider S, Leichert LIO, Benedikt J, Awakowicz P, Bandow JE. A dielectric barrier discharge terminally inactivates RNase A by oxidizing sulfur-containing amino acids and breaking structural disulfide bonds. J Phys D Appl Phys. 2015;48:494003. Scholar
  19. 19.
    O’Connell D, Cox LJ, Hyland WB, McMahon SJ, Reuter S, Graham WG, Gans T, Currell FJ. Cold atmospheric pressure plasma jet interactions with plasmid DNA. Appl Phys Lett. 2011;98:043701. Scholar
  20. 20.
    Boxhammer V, Li YF, Köritzer J, Shimizu T, Maisch T, Thomas HM, Schlegel J, Morfill GE, Zimmermann JL. Investigation of the mutagenic potential of cold atmospheric plasma at bactericidal dosages. Mutat Res. 2013;753:23–8.CrossRefGoogle Scholar
  21. 21.
    Kluge S, Bekeschus S, Bender C, Benkhai H, Schkell A, Below H, Stope MB, Kramer A. Investigating the mutagenicity of a cold argon-plasma jet in an HET-MEN model. PLoS One. 2016;11(9):e0160667. Scholar
  22. 22.
    Wende K, Bekeschus S, Schmidt A, Jatsch L, Hasse S, Weltmann KD, Masur K, von Woedtke T. Risk assessment of a cold argon plasma jet in respect to its mutagenicity. Mutat Res Genet Toxicol Environ Mutagen. 2016;798–799:48–54.CrossRefGoogle Scholar
  23. 23.
    Wende K, Straßenburg 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.CrossRefGoogle Scholar
  24. 24.
    Isbary G, Köritzer J, Mitra A, Li Y-F, Shimizu T, Schroeder J, Schlegel J, Morfill GE, Stolz W, Zimmermann JL. Ex vivo human skin experiments for the evaluation of safety of new cod atmospheric plasma devices. Clin Plasma Med. 2013;1:36–44. Scholar
  25. 25.
    Schmidt A, von Woedtke T, Stenzel J, Lindner T, Polei S, Vollmar B, Bekeschus S. One year follow-up risk assessment in SKH-1 Mice and wounds treated with an argon plasma jet. Int J Mol Sci. 2017;18:868. Scholar
  26. 26.
    Metelmann HR, Vu TT, Do HT, Le TNB, Hoang THA, Phi TTT, Luong TML, Doan VT, Nguyen TTH, Nguyen THM, Nguyen TL, Le DQ, Le TKX, von Woedtke T, Bussiahn R, Weltmann KD, Khalili R, Podmelle F. Scar formation of laser skin lesions after cold atmospheric pressure plasma (CAP) treatment: a clinical long term observation. Clin Plasma Med. 2013;1:30–5. Scholar
  27. 27.
    Ke Z, Huang Q. Assessment of damage of glutathione by glow discharge plasma at the gas-solultion interface through Raman spectroscopy. Plasma Process Polym. 2013;10:181–8.CrossRefGoogle Scholar
  28. 28.
    Klinkhammer C, Verlackt C, Smilowicz D, Kogelheide F, Bogaerts A, Metzler-Nolte N, Stapelmann K, Havenith M, Lackmann J-W. Elucidation of plasma-induced chemical modifications on glutathione and glutathione disulfide. Sci Rep. 2017;7(1):13828.CrossRefGoogle Scholar
  29. 29.
    Arndt S, Unger P, Wacker E, Shimizu T, Heinlin J, Li Y-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.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    Schmidt A, Wende K, Bekeschus S, Bundscherer L, Barton A, Ottmüller K, Weltmann K-D, Masur K. Non-thermal plasma treatment is associated with changes in transcriptome of human epithelial skin cells. Free Radic Res. 2013;47:577–92. Scholar
  32. 32.
    Bekeschus S, von Woedtke T, Kramer A, Weltmann KD, Masur K. Cold physical plasma treatment alters redox balance in human immune cells. Plasma Med. 2013;3:267–78.CrossRefGoogle Scholar
  33. 33.
    Bekeschus S, Schmidt A, Weltmann KD, von Woedtke T. The plasma jet kINpen—a powerful tool for wound healing. Clin Plasma Med. 2016;4:19–28.CrossRefGoogle Scholar
  34. 34.
    Stoffels E, Roks AJM, Deelman LE. Delayed effects of cold atmospheric plasma on vascular cells. Plasma Process Polym. 2008;5:599–605. Scholar
  35. 35.
    Bekeschus S, Iseni S, Reuter S, Masur K, Weltmann KD. Nitrogen shielding of an argon plasma jet and its effects on human immune cells. IEEE Trans Plasma Sci. 2015;43:776–81. Scholar
  36. 36.
    Schmidt A, Dietrich S, Steuer A, Weltmann KD, von Woedtke T, Masur K, Wende K. Non-thermal plasma activates human keratinocytes by stimulation of antioxidant and phase II pathways. J Biol Chem. 2015;290:6731–50.CrossRefGoogle Scholar
  37. 37.
    Weltmann K-D, Kindel E, Brandenburg R, Meyer C, Bussiahn R, Wilke C, von Woedtke T. Atmospheric pressure plasma jet for medical therapy: plasma parameters and risk estimation. Contrib Plasma Phys. 2009;49:634–40. Scholar
  38. 38.
    Isbary G, Zimmermann JL, Shimizu T, Li Y-F, Morfill GE, Thomas HM, Steffes B, Heinlin J, Karrer S, Stolz W. Non-thermal plasma-More than five years of clinical experience. Clin Plasma Med. 2013;1:19–23.CrossRefGoogle Scholar
  39. 39.
    Isbary G, Shimizu T, Zimmermann JL, Heinlin J, Al-Zaabi S, Rechfeld M, Morfill GE, Karrer S, Stolz W. Randomized placebo-controlled clinical trial shoed cold atmospheric argon plasma relieved acute pain and accelerated healing. Clin Plasma Med. 2014;2:50–5.CrossRefGoogle Scholar
  40. 40.
    Emmert S, Brehmer F, Hänßle H, Helmke A, Mertens N, Ahmed R, Simon D, Wandke D, Maus-Friedrichs W, Däschlein g SMP, Viöl W. Atmospheric pressure plasma in dermatology: ulcus treatment and much more. Clin Plasma Med. 2013;1:24–9. Scholar
  41. 41.
    Heinlin J, Isbary G, Stolz W, Zeman F, Landthaler M, Morfill G, Shimizu T, Zimmermann JL, Karrer S. A randomized two-sided placebo-controlled study on the efficacy and safety of atmosperic non-thermal argon plasma for pruritus. J Eur Acad Dermatol Venereol. 2013;27:324–31. Scholar
  42. 42.
    Heinlin J, Zimmermann JL, Zeman F, Bunk W, Isbary G, Landthaler M, Maisch T, Monetti R, Morfill G, Shimizu T, Steinbauer J, Stolz W, Karrer S. Randomized placebo-controlled human pilot study of cold atmospheric argon plasma on skin graft donor site. Wound Repair Regen. 2013;21:800–7. Scholar
  43. 43.
    Klebes M, Lademann J, Philipp S, Ulrich C, Patzelt A, Ulmer M, Kluschke F, Kramer A, Weltmann KD, Serry W, Lange-Asschenfeldt B. Effects of tissue-tolerable plasma on psoriasis vulgaris treatment compared to conventional local treatment: a pilot study. Clin Plasma Med. 2014;2:22–7.CrossRefGoogle Scholar
  44. 44.
    Brehmer F, Haenssle HA, Daeschlein G, Ahmed R, Pfeiffer S, Görlitz A, Simon D, Schön MP, Wandke D, Emmert S. Allevation of chronic venous leg ulcers with a hand-held dielectric barrier discharge plasma generator (PlasmaDerm® VU-2010): results of a monocentric, two-armed, open, prospective, randomized and controlled trial (NCT01415622). J Eur Acad Dermatol Venereol. 2015;29:148–55. Scholar
  45. 45.
    Ulrich C, Kluschke F, Patzelt A, Vandersee S, Czaika VA, Richter H, Bob A, von Hutten J, Painsi C, Hügel R, Kramer A. Clinical use of cold atmospheric pressure argon plasma in chronic leg ulcers: a pilot study. J Wound Care. 2015;24:196, 198–200, 202–203.CrossRefGoogle Scholar
  46. 46.
    Schuster M, Rana A, Hauschild A, Seebauer C, Bauer G, Metelmann P, Rutkowski R, Shojaei RK, von Woedtke T. Why are there no side effects in plasma treatment of oral cancer? Clin Plasma Med. 2018 (in press).Google Scholar
  47. 47.
    Metelmann H-R, Nedrelow DS, Seebauer C, Schuster M, von Woedtke T, Weltman K-D, Kindler S, Metelmann PH, Finkelstein SE, von Hoff DD, Podmelle F. Head and neck cancer treatment and physical plasma. Clin Plasma Med. 2015;3:17–23.CrossRefGoogle Scholar
  48. 48.
    Schuster C, Seebauer R, Rutkowski A, Hauschild F, Podmelle C, Metelmann B, Metelmann T, von Woedtke S, 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.CrossRefGoogle Scholar
  49. 49.
    Bekeschus S, Masur K, Kolata J, Wende K, Schmidt A, Bundscherer L, Barton A, Kramer A, Bröker B, Weltmann K-D. Human mononuclear cell survival and proliferation is modulated by cold atmospheric plasma jet. Plasma Process Polym. 2013;10:706–13. Scholar
  50. 50.
    Bekeschus S, Kolata J, Winterbourn C, Kramer A, Turner R, Weltmann K-D, Bröker B, Masur K. Hydrogen peroxide: a central player in physical plasma-induced oxidative stress in human blood cells. Free Radic Res. 2014;48:542–9. Scholar
  51. 51.
    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 Process Polym. 2012;9:417–24.CrossRefGoogle Scholar
  52. 52.
    Dahl TA, Middenand WR, Hartman PE. Pure singlet oxygen cytotoxicity for bacteria. Photochem Photobiol. 1987;46:345–52.CrossRefGoogle Scholar
  53. 53.
    Maisch T, Baier J, Franz B, Maier M, Landthaler M, Szeimies R-M, Bäumler W. The role of singlet oxygen and oxygen concentration in photodynamic inactivation of bacteria. Proc Natl Acad Sci U S A. 2007;104:7223–8.CrossRefGoogle Scholar
  54. 54.
    Schafer M, Schmitz C, Horneck G. High sensitivity of Deinococcus radiodurans to photodynamically-produced singlet oxygen. Int J Radiat Biol. 1998;74:249–53.CrossRefGoogle Scholar
  55. 55.
    Tatsuzawa H, Maruyama T, Misawa N, Fujimori K, Hori K, Sano Y, Kambayashi Y, Nakano M. Inactivation of bacterial respiratory chain enzymes by singlet oxygen. FEBS Lett. 1998;439:329–33.CrossRefGoogle Scholar
  56. 56.
    Dahl TA. Direct exposure of mammalian cells to pure endogenous singlet oxygen (1-delta-GO2). Photochem Photobiol. 1993;57:248–54.CrossRefGoogle Scholar
  57. 57.
    Nagata JY, Hioka N, Kimura E, Batistela VR, Terada RSS, Graciano AX, Baesso ML, Hayacibara MF. Antibacterial photodynamic therapy for dental caries: evaluation of the photosensitizer used and light source properties. Photodiagn Photodyn Ther. 2012;9:122–31.CrossRefGoogle Scholar
  58. 58.
    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 Process Polym. 2010;7:264–73.CrossRefGoogle Scholar
  59. 59.
    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;130:2194–85.CrossRefGoogle Scholar
  60. 60.
    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. Scholar
  61. 61.
    Walk RM, Snyder JA, Srinivasan P, Kirsch J, Diaz SO, Blanco FC, Shashuin A, Keidar M, Sandler AD. Cold atmospheric plasma for the ablative treatment of neuroblastoma. J Pediatr Surg. 2013;48:67–73.CrossRefGoogle Scholar
  62. 62.
    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.CrossRefGoogle Scholar
  63. 63.
    Cheng X, Sherman J, Murphy W, Ratovitski E, Canady J, Keidar M. The effect of tuning cold plasma composition on glioblastoma cell viability. PLoS One. 2014;9:e98652.CrossRefGoogle Scholar
  64. 64.
    Chang JW, Kang SU, Shin YS, Kim KI, Seo SJ, Yang SS, Lee JS, Moon E, Lee K, Kim CH. Non-thermal atmospheric pressure plasma inhibits thyroid papillary cancer cell invasion via cytoskeletal modulation, altered mmp-2/−9/upa activity. PLoS One. 2014;9:e92198.CrossRefGoogle Scholar
  65. 65.
    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.CrossRefGoogle Scholar
  66. 66.
    Von Behr M, Masur K, Hackbarth C, Bekeschus S, Wende K, Kantz L, Heidecke C-D, von Bernstorff PLI. Effects of tissue tolerable plasma in combination with gemcitabine on pancreatic cancer cells. Pancreatology. 2015;15:S36–7.CrossRefGoogle Scholar
  67. 67.
    Ishaq M, Han ZJ, Kumar S, Evans MOM, Ostrikov K. Atmospheric plasma- and TRAIL-induced apoptosis in TRAIL-resistant colorectal cancer cells. Plasma Process Polym. 2015;12:574–82.CrossRefGoogle Scholar
  68. 68.
    Hattori N, Yamada S, Torii K, Takeda S, Nakamura K, Tanaka H, Kajiyama H, Kanda M, Fujii T, Nakayama G, Sugimoto H, Koike M, Nomoto S, Fujiwara M, Mizuno M, Hori M, Kodera Y. Effectiveness of plasma treatment on pancreatic cancer cells. Int J Oncol. 2015;47:1655–62.CrossRefGoogle Scholar
  69. 69.
    Ikeda J-I, Tsuruta Y, Nojima S, Sakakita H, Hori M, Ikehara Y. Anti-cancer effects of nonequilibrium atmospheric pressure plasma on cancer-initiating cells in human endometrioid adenocarcinoma cells. Plasma Process Polym. 2015;12:1370–6.CrossRefGoogle Scholar
  70. 70.
    Weiss M, Gümbel D, Hanschmann E-M, Mandelkow R, Gelbrich N, Zimmermann U, Walther R, Ekkernkamp A, Sckell A, Kramer A, Burchardt M, Lillig CH, Stope MB. Cold atmospheric plasma treatment induces anti-proliferative effects in prostate cancer cells by redox and apoptotic signaling pathways. PLoS One. 2015;10:e0130350. Scholar
  71. 71.
    Bekeschus S, Wende K, Hefny MM, Rödder K, Jablonowski H, Schmidt A, von Woedtke T, Weltmann K-D, Benedikt J. Oxygen atoms are critical in rendering THP-1 leukaemia cells susceptible to cold physical plasma-induced apoptosis. Sci Rep. 2017;7:2791.CrossRefGoogle Scholar
  72. 72.
    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.CrossRefGoogle Scholar
  73. 73.
    Mizuno K, Yonetamari K, 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.CrossRefGoogle Scholar
  74. 74.
    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.CrossRefGoogle Scholar
  75. 75.
    Keidar M, Shashurin A, Volotskova O, Stepp MA, Srinivasan P, Sandler A, Trink B. Cold atmospheric plasma in cancer therapy. Phys Plasmas. 2013;20:057101. Scholar
  76. 76.
    Keidar M. Plasma for cancer treatment. Plasma Sources Sci Technol. 2015;24:033001.CrossRefGoogle Scholar
  77. 77.
    Schlegel J, Köritzer J, Boxhammer V. Plasma in cancer treatment. Clin Plasma Med. 2013;1:2–7.CrossRefGoogle Scholar
  78. 78.
    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. 2014;42:3760–4. Scholar
  79. 79.
    Barekzi N, Laroussi M. Effects of low temperature plasmas on cancer cells. Plasma Process Polym. 2013;10:1039–50.CrossRefGoogle Scholar
  80. 80.
    Laroussi M. From killing bacteria to destroying cancer cells: 20 years of plasma medicine. Plasma Process Polym. 2014;11:1138–41.CrossRefGoogle Scholar
  81. 81.
    Laroussi M. Low-temperature plasma jet for biomedical applications: a review. IEEE Trans Plasma Sci. 2015;43:703–12.CrossRefGoogle Scholar
  82. 82.
    Laroussi M, Mohades S, Barekzi N. Killing adherent and nonadherent cancer cells with the plasma pencil. Biointerphases. 2015;10:029401.CrossRefGoogle Scholar
  83. 83.
    Ratovitski EA, Heng X, Yan D, Sherman JH, Canady J, Trink B, Keidar M. Anti-Cancer Therapies of 21st century: novel approach to treat human cancers using cold atmospheric plasma. Plasma Process Polym. 2014;11:1128–37.CrossRefGoogle Scholar
  84. 84.
    Yan DY, Sherman JH, Keidar M. Cold atmospheric plasma, a novel promising anti-cancer treatment modality. Oncotarget. 2017;8:15977–95.Google Scholar
  85. 85.
    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.CrossRefGoogle Scholar
  86. 86.
    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.CrossRefGoogle Scholar
  87. 87.
    Kaushik N, Kumar N, Kim CH, Kaushik NK, Choi EH. Dielectric barrier discharge plasma efficiently delivers an apoptotic response in human monocytic lymphoma. Plasma Process Polym. 2014;11:1175–87. Scholar
  88. 88.
    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. Scholar
  89. 89.
    Kim SJ, Chung TH. Cold atmospheric plasma jet-generated RONS and their selective effects on normal and carcinoma cells. Sci Rep. 2016;6:20332. Scholar
  90. 90.
    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. Scholar
  91. 91.
    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;3:398–16. Scholar
  92. 92.
    Ishaq M, Evans M, Ostrikov K. Effect of atmospheric gas plasmas on cancer cell signaling. Int J Cancer. 2013;134:1517–28. Scholar
  93. 93.
    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, Gerlin 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.CrossRefGoogle Scholar
  94. 94.
    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. Scholar
  95. 95.
    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.CrossRefGoogle Scholar
  96. 96.
    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.CrossRefGoogle Scholar
  97. 97.
    Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.CrossRefGoogle Scholar
  98. 98.
    Hodge JW, Garnett CT, Farsaci B, Palena C, Tsang K-Y, Ferrone S, Gameiro SR. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer. 2013;133:624–37.CrossRefGoogle Scholar
  99. 99.
    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 Process Polym. 2015;12:1392–9.CrossRefGoogle Scholar
  100. 100.
    Miller V, Lin A, Fridman A. Why target immune cells for plasma treatment of cancer. Plasma Chem Plasma Process. 2016;36:259–68.CrossRefGoogle Scholar
  101. 101.
    Bauer G. Signal amplification by tumor cells: clue to the understanding of the antitumor effects of cold atmospheric plasma and plasmaactivated medium. IEEE Trans Rad Plasma Med Sci. 2017;1(6):1–12.Google Scholar
  102. 102.
    Heinzelmann S, Bauer G. Multiple protective functions of catalase against intercellular apoptosis-inducing ROS signaling of human tumor cells. Biol Chem. 2010;391:675–93.CrossRefGoogle Scholar
  103. 103.
    Bauer G. Targeting extracellular ROS signaling of tumor cells. Anticancer Res. 2014;34:1467–82.PubMedGoogle Scholar
  104. 104.
    Bauer G. Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells. Redox Biol. 2015;6:353–71.CrossRefGoogle Scholar
  105. 105.
    Bauer G. Targeting the protective catalase of tumor cells with cold atmospheric plasma-treated medium (PAM). Anticancer Agents Med Chem. 2017.  https.// 10.2174/1871520617666170801103708.
  106. 106.
    Chiang CLL, Ledermann JA, Rad AN, Katz DR, Chain BM. Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells. Cancer Immunol Immunother. 2006;55:1384–95.CrossRefGoogle Scholar
  107. 107.
    Biedron R, Konopinski MK, Marcinkiewicz J, Jozefowski S. Oxidation by neutrophil-derived HOCl 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.CrossRefGoogle Scholar
  108. 108.
    Griffiths HR. Is the generation of neo antigenic determinants by free radicals central to the development of autoimmune rheumatoid disease? Autoimmun Rev. 2008;7:544–9. Scholar
  109. 109.
    Kurien BT, Scotfield RH. Autoimmunity and oxidatively modified autoantigens. Autoimmun Rev. 2008;7:567–73. Scholar
  110. 110.
    Riethmüller M, Burger N, Bauer G. Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling. Redox Biol. 2015;6:157–68.CrossRefGoogle Scholar
  111. 111.
    Bauer G. Autoamplificatory singlet oxygen generation sensitizes tumor cells for intercellular apoptosis-inducing signaling. Mech Ageing Dev. 2017.
  112. 112.
    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.CrossRefGoogle Scholar
  113. 113.
    Yan DY, 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.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Georg Bauer
    • 1
  • David B. Graves
    • 2
  • Matthias Schuster
    • 3
  • Hans-Robert Metelmann
    • 3
  1. 1.Institute of Virology, Medical Center and Faculty of MedicineUniversity of FreiburgFreiburgGermany
  2. 2.Department of Chemical and Biomolecular EngineeringUniversity of California at BerkeleyBerkeleyUSA
  3. 3.Department of Oral and Maxillofacial Surgery/Plastic SurgeryUniversity Medicine GreifswaldGreifswaldGermany

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