Anticancer Effects of Plasma-Treated Water Solutions from Clinically Approved Infusion Liquids Supplemented with Organic Molecules

Abstract

Water solutions treated by cold atmospheric plasmas (CAPs) currently stand out in the field of cancer treatment as sources of exogenous blends of reactive oxygen and nitrogen species (RONS). It is well known that the balance of RONS inside both eukaryotic and prokaryotic cells is directly involved in physiological as well as pathological pathways. Also, organic molecules including phenols could exert promising anticancer effects, mostly attributed to their prooxidant ability in vitro and in vivo to generate RONS like O 2 − , H 2 O 2 , and a mixture of potentially cytotoxic compounds. By our vision of combining the efficacy of plasma-produced RONS and the use of organic molecules, we could synergistically attack cancer cells; yet, so far, this combination, to the best of our knowledge, has been completely unexplored. In this study, L-tyrosine, an amino acid with a phenolic side chain, is added to a physiological solution, often used in clinical practice (SIII) to be exposed to plasma. The efficacy of the gas plasma-oxidized SIII solution, containing tyrosine, was evaluated on four cancer cell lines selected from among tumors with poor prognosis (SHSY-5Y, MCF-7, HT-29, and SW-480). The aim was to induce tumor toxicity and trigger apoptosis pathways. The results clearly indicate that the plasma-treated water solution (PTWS) reduced cell viability and oxygen uptake due to an increase in intracellular ROS levels and activation of apoptosis pathways in all investigated cancer cells, which may be related to the activation of the mitochondrial-mediated and p-JNK/caspase-3 signaling pathways. This research offers improved knowledge about the physiological mechanisms underlying cancer treatment and a valid method to set up a prompt, adequate, and effective cancer treatment in the clinic.

Comparing Redox and Intracellular Signalling Responses to Cold Plasma in Wound Healing and Cancer

“…Furthermore, higher CP exposure can kill malignant cells through CHOP-dependent apoptosis as a result of prolonged UPR activity [136,197,198] and inhibition of Nrf2/ARE via Akt degradation and p53 [109,170]. Additionally, CP treatment could differentially modulate different MAPK pathways depending on the exposure time and whether the cells were malignant or non-malignant [108,132,150,203,204,220]. Similarly, CP has been shown to modulate PI3K/Akt in a bimodal fashion, with lower CP exposures transiently activating Akt to promote survival, proliferation and angiogenesis during tissue repair [128,240], while higher CP exposures causing severe redox stress would lead to heavily suppressed or completely ablated Akt expression and activity, apoptosis and autophagy [94,102,129,134,135,177].…”

“…Exposure of cervical cancer cells (HeLa) to CP reduced ERK1/2 and JNK activity, while JNK and p38 activity was reduced in ovarian cancer cells exposed to PAM, leading to significantly diminished invasiveness (cell migration) and matrix metalloproteinase 9 (MMP9) activity [132,203]. However, more lethal exposures to CP markedly activate JNK and p38 in several cancer cell types, including HeLa cells, neuroblastoma, prostate cancer, lung carcinoma, hepatoma, breast cancer, and colorectal adenocarcinoma cell lines, leading to cell cycle arrest, then bcl2 proapoptotic proteins bax and bak initiate mitochondria-dependent cell death via cytochrome c release and caspase 9/3-driven apoptosis [101,108,127,150,204]. In several cancer cell types with high gasdermin E (GSDME) expression, CP treatment also led to pyroptosis [127]; a highly inflammatory manifestation of programmed necrosis caused by gasdermin (including GSDME) cleavage by caspase 3 leading to GSDMN pore formation that perforates the cell membrane [205][206][207][208].…”

“…Several studies have directly compared malignant and normal human cell responses to CP and PAL under constant or very similar cell culture conditions [69,100,101,125,129,150,213,216,219,248,[257][258][259][260][261]. Studies have even compared the responses of multiple cell lines of the same cancer type or different cancers using different conditions for each cell line to investigate CP sensitivity [127,175,204,254]. Although useful insight may still be garnered, it is problematic to compare responses between cell types, particularly under different culture media conditions, and may lead to inaccurate conclusions.…”

Cold atmospheric‐pressure plasma selectively inhibits glioblastoma via DNA damage and AKT dephosphorylation in vitro and in vivo

“…[ 10–12 ] In vitro studies identified that plasma‐treated water solution could reduce cancer cell (SHSY‐5Y, MCF‐7, HT‐29, and SW‐480) viabilities by increasing intracellular ROS levels and activations of apoptotic pathways such as phospho‐Jun N‐terminal kinase (p‐JNK)/caspase‐3 signaling pathways. [ 13 ] Meanwhile, it has been indicated that CAP induces glioblastoma cell apoptosis by activating the JNK or caspase pathway. [ 14,15 ] Besides, CAP was found to restore the sensitivity in chemoresistant glioma cells in vitro, and studies have also shown that CAP combined with nanoparticle or temozolomide (TMZ) could produce synergistic effects in vitro.…”

Comparing Redox and Intracellular Signalling Responses to Cold Plasma in Wound Healing and Cancer

“…These molecules also decrease the pH of the liquid, creating an antimicrobial environment capable of effectively killing bacteria [33][34][35][36] and eliciting various redox-dependent cellular signalling responses in eukaryotic and cancerous cells. Additionally, PAL have been shown to exhibit the desired biological effects when used after the short-lived species are degraded post-plasma activation, indicating that PAL could be storable for future use when sealed and stored at appropriate temperature [18,[37][38][39]. Consequently, PAL has the advantages of being potentially storable, transportable, with no risk of heating tissue, and is more feasible for use in busy clinics.…”