Cold atmospheric plasma, a novel promising anti-cancer treatment modality

Abstract

Over the past decade, cold atmospheric plasma (CAP), a near room temperature ionized gas has shown its promising application in cancer therapy. Two CAP devices, namely dielectric barrier discharge and plasma jet, show significantly anti-cancer capacity over dozens of cancer cell lines in vitro and several subcutaneous xenograft tumors in vivo. In contrast to conventional anti-cancer approaches and drugs, CAP is a selective anti-cancer treatment modality. Thus far establishing the chemical and molecular mechanism of the anti-cancer capacity of CAP is far from complete. In this review, we provide a comprehensive introduction of the basics of CAP, state of the art research in this field, the primary challenges, and future directions to cancer biologists.

Keywords: cancer treatment; cold plasma; reactive species; selectivity.

Figure 1. The physical description of plasmas

a. Schematic illustration of the four fundamental states of matter. The triangular tails represent the thermal motion strength of particles. b. Schematic illustration of the thermal plasma and the cold plasma. Brown balls, violet balls, and iridescent balls represent the neutral atoms, the positively charged ions, and electrons, respectively.

Figure 2. The plasma jet device and dielectric barrier discharge (DBD) device are two main CAP devices used in plasma medicine

The same components in the plasma jet and DBD are drawn with the same colors. The left inset is reproduced with permission from Alan Siu, et al., PLoS ONE, 10(6), e0126313 (2015). Copyright 2015 Public Library of Science. The right inset is reproduced with permission from Sameer Kalghatgi, et al., PLoS ONE, 6(1), e16270 (2011). Copyright 2011 Public Library of Science.

Figure 3. The research status of the application of CAP on cancer treatment by 2016

a. Publication number. *: by the end of September. b. The journal types of articles. c. Cancers in articles. d. Plasma devices in articles.

Figure 4. Two basic strategies to use CAP

a. Direct CAP treatment on cancer cells in vitro or on subcutaneous xenografted tumors in vivo. b. Indirect CAP treatment on solutions mainly medium. These PSM will be used to inhibit the growth of cancer cells seeded in multi-wells plate or the tumor tissues in mice.

Figure 5. Schematic illustration for the interaction between CAP and cells

in vitro and in vivo. Abbreviations: E & M: electromagnetic field, UV: ultraviolet. The dissolved reactive oxygen/nitrogen species in the culture medium have been regarded as the main factor causing the death of cancer cells in vitro. However, the inhibited growth of subcutaneous tumor tissues through the treatment of CAP above the skin is still a puzzled question in plasma medicine.

Figure 6. The anti-cancer effect of CAP in mice model

(a) Image of mouse with two tumors before and after the plasma jet treatment for 24 hr. The subcutaneous tumors are grown from the seeded bladder cancer cells (SCaBER) [46]. Reproduced with permission from M. Keidar, et al., British Journal of Cancer, 105, 1295 (2011). Copyright 2011 Cancer Research UK. (b) Cold plasma treatment effect on the growth of established tumor in a murine melanoma model [46]. Reproduced with permission from M. Keidar, et al., British Journal of Cancer, 105, 1295 (2011). Copyright 2011 Cancer Research UK. (c) Images of nude mice bearing subcutaneous NOS2TR tumors before and after the injection of the cold plasma-stimulated medium. Green arrowheads indicate tumor site [71]. Reproduced with permission from F Utsumi, et al., PLoS ONE, 8, e81576 (2013). Copyright 2013 Public Library of Science..

Figure 7. A general summary for the anti-cancer mechanism of CAP

in vitro based on publications by the end of 2015. Shortly, the CAP-originated reactive species will cause a noticeable rise of intracellular ROS, which weakens the intracellular anti-oxidant system and further causes serious DNA double-strand break. As a result, cell cycle arrest and apoptosis based on mitochondrion-pathway or tumor necrosis factor receptor-pathway occur. Abbreviations: ROS: reactive oxygen species, RNS: reactive nitrogen species, Nox: NADPH oxidases, AQP: aquaporins, TNFR: tumor necrosis factor receptor, FAK, focal adhesion kinase, Src: Src kinase, SOD: superoxide dismutase, GSH: glutathione, Prx: peroxiredoxin, NADPH: reduced nicotinamide adenine dinucleotide phosphate, mTOR: mechanistic target of rapamycin, DNA: deoxyribonucleic acid, DSB: double-strand break, ATM: ataxia telangiectasia mutated, mRNA: messenger ribonucleic acid, ASK: apoptosis signal-regulating kinase, JNK: c-Jun N-terminal kinase.

Figure 8. The modified selective model based on the distinct expression of AQPs and catalase in cancer cells and normal cells

Cancer cells express more AQPs and less catalase than homologous normal cells in many cases.