RESUMEN
Non-thermal plasma (NTP) is applicable to living cells and has emerged as a novel technology for cancer therapy. Plasma-activated medium (PAM), which is prepared by the irradiation of culture medium with NTP, induces cell death in cancer cells. However, difficulties are associated with applying PAM to the clinical phase because culture media cannot be used for medical treatments. The objectives of the present study were to demonstrate the inhibitory effects of plasma-activated lactated Ringer's solution (PAL) on the viability of the A549 cancer cell line and elucidate the underlying mechanisms. The anti-tumor activity of PAL was significantly stronger than that of PAM, whereas their concentrations of H2O2 and nitrite were similar. Lactated Ringer's solution (Lac-R) consists of lactate and three types of inorganic salts. The results showing that NTP irradiation of the lactate solution rather than the inorganic salt solution induced the inactivation of catalase were dependent on the presence or absence of nitrite in these solutions. We detected nitrotyrosine in A549â¯cells treated with PAM or PAL, and the addition of catalase to PAM rather than to PAL reduced its production. The PAL treatment of A549â¯cells led to mitochondrial dysfunction with the down-regulation of NF-κB-Bcl2 signaling.
Asunto(s)
Antineoplásicos/farmacología , Medios de Cultivo/farmacología , Gases em Plasma/química , Lactato de Ringer/farmacología , Células A549 , Antineoplásicos/química , Antineoplásicos/toxicidad , Catalasa/química , Supervivencia Celular/efectos de los fármacos , Medios de Cultivo/química , Medios de Cultivo/toxicidad , Humanos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/toxicidad , Queratinocitos/efectos de los fármacos , Ácido Láctico/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Nitritos/química , Lactato de Ringer/química , Lactato de Ringer/toxicidad , Transducción de Señal/efectos de los fármacos , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
The number of potential applications of non-thermal atmospheric pressure plasma (NTAPP) discharges in medicine, particularly in cancer therapy, has increased in recent years. NTAPP has been shown to affect cells not only by direct irradiation, but also by an indirect treatment with previously prepared plasma-activated medium (PAM). Histone deacetylase (HDAC) inhibitors have the potential to enhance susceptibility to anticancer drugs and radiation. The aim of the present study was to demonstrate the advantage of the combined application of PAM and HDAC inhibitors on A549 cancer cell survival and elucidate the underlying mechanisms. Cell death with DNA breaks in the nucleus was greater using combined regimens of PAM and HDAC inhibitors such as trichostatin A (TSA) and valproic acid (VPA) than a single PAM treatment and was accompanied by the activation of poly (ADP-ribose) polymerase-1 (PARP-1), depletion of ATP, and elevations in intracellular calcium levels. Moreover, the expression of Rad 51, a DNA repair factor in homologous recombination pathways, was significantly suppressed by the treatment with HDAC inhibitors. These results demonstrate that HDAC inhibitors may synergistically induce the sensitivity of cancer cells to PAM components.