Electroporation Enhances the Anticancer Effects of Novel Cu(II) and Fe(II) Complexes in Chemotherapy-Resistant Glioblastoma Cancer Cells.

Schiff base ligand (L) was obtained by condensation reaction between 4-aminopyrimidin-2(1H)-one (cytosine) with 2-hydroxybenzaldehyde. The synthesized Schiff base was used for complexation with Cu(II) and Fe(II) ions used by a molar (2 : 1 mmol ration) in methanol solvent. The structural features of ligand, Cu(II), and Fe(II) metal complexes were determined by standard spectroscopic methods (FT-IR, elemental analysis, proton and carbon NMR spectra, UV/VIS, and mass spectroscopy, magnetic susceptibility, thermal analysis, and powder X-ray diffraction). The synthesized compounds (Schiff base and its metal complexes) were screened in terms of their anti-proliferative activities in U118 and T98G human glioblastoma cell lines alone or in combination with electroporation (EP). Moreover, the human HDF (human dermal fibroblast) cell lines was used to check the bio-compatibility of the compounds. Anti-proliferative activities of all compounds were ascertained using an MTT assay. The complexes exhibited a good anti-proliferative effect on U118 and T98G glioblastoma cell lines. In addition, these compounds had a negligible cytotoxic effect on the fibroblast HDF cell lines. The use of compounds in combination with EP significantly decreased the IC50 values compared to the use of compounds alone (p<0.05). These results show that newly synthesized Cu(II) and Fe(II) complexes can be developed for use in the treatment of chemotherapy-resistant U118 and T98G glioblastoma cells and that treatment with lower doses can be provided when used in combination with EP.

Anticancer activity of methotrexate in electrochemotherapy and electrochemotherapy plus ionizing radiation treatments in human breast cancer cells.

Traditional cancer treatments, such as chemotherapy and radiotherapy have several limitations. Therefore, their performance must be enhanced with combined methods. The purpose of this study is to investigate both the efficacy of electroporation (EP) on the activity of methotrexate (MTX) and the combined treatment of electrochemotherapy (ECT) + ionizing radiation (IR) in MCF-7 cancer cells. Different treatment techniques, such as EP, MTX, MTX + EP (ECT), 140 kV X-ray alone (IR_140kV), 500 kV X-ray alone (IR_500kV), ECT + IR_140kV and ECT + IR_500kV, were applied to cancer cells. Eight electric pulse trains with square wave (800 V/cm, 100 µs and 1 Hz) were used in EP and ECT applications. The MTT assay was used to assess the efficacy of the therapies used. When the EP, MTX, ECT, IR_140kV, and IR_500kV treatment groups were compared to the control group, there was a significant reduction in MCF-7 cancer cells viability (p < 0.05). ECT was the most effective of these treatments, decreasing viability of cancer cells to 58.78%. The ECT + IR_140kV and ECT + IR_500kV groups were compared to the ECT group to examine the impact of X-ray radiation on ECT treatment. When compared to the ECT alone group, both groups that exposed to X-rays after ECT had a significant decrease in cell viability (p < 0.05). Furthermore, viability of MCF-7 cells reduced to 46.38% in the ECT + IR_140kV group and 35.89% in the ECT + IR_500kV group. In conclusion, the study shows that the cytotoxicity of MTX is significantly increased in ECT treatment compared to standard chemotherapy (p < 0.05). In addition, ECT + IR combined therapy application is much more effective than MTX or ECT treatments alone.

Synthesis, characterization, antioxidant and anticancer activities of a new Schiff base and its M(II) complexes derived from 5-fluorouracil.

In this study, Schiff base ligand was obtained from the condensation reaction of benzene-1,2-diamine and 5-fluoropyrimidine-2,4(1H,3H)-dione (5-FU). Metal(II) complexes were synthesized with Fe(II), Co(II) and Ni(II) chloride salts. The synthesized ligand and metal complexes were characterized by FT-IR, UV-vis, 1H-13C NMR, elemental analyses, mass spectroscopy, magnetic moments, molar conductivity and thermogravimetric analysis studies. With the help of different techniques reveal Fe(II), Co(II) and Ni(II) complexes have exhibited tetrahedral and octahedral geometry. Ligand acted as bidentate and it binds metal(II) ions through deprotonated-NH, imine-N atom and carbonyl-O atom, respectively. DPPH, ABTS, FRAP, CUPRAC and total antioxidant activity methods were used to determine the antioxidant properties of ligand and metal complexes. According to the results, the synthesized compounds showed very high antioxidant activity compared to 5-FU. The cytotoxicities of the synthesized compounds were performed on MCF-7 (human breast cancer) and L-929 (fibroblast) cell lines using the MTT assay. In addition, the effect of electroporation (EP) on the cytotoxicity of the compounds was investigated. Our results demonstrated that novel Co(II) and Ni(II) complexes show potential as new anticancer agents and ECT may be a viable treatment option for breast cancer.

Influence of extremely low-frequency magnetic field on chemotherapy and electrochemotherapy efficacy in human Caco-2 colon cancer cells.

Although chemotherapy (CT) has some adverse effects on healthy tissues and cells, it is widely preferred for treating patients with cancer. Drug resistance is one of the major impediments to successful cancer treatment. Electrochemotherapy (ECT) is a technique where cancer cells are rendered permeable to medications. Thanks to this permeability, the dose of the medication required for cancer treatment decreases. Our aim in this study is to examine the effects of short-term extremely low-frequency magnetic fields (ELF-MFs) on CT and ECT treatments in Caco-2 colon cancer cells. The Caco-2 cancer cells were treated with 5-fluorouracil (5-FU, 50 µM) and ECT (strength:1125 V/cm, duration:100 µs, frequency:1 Hz), alone as well as in combinations with ELF-MF (4 mT, 10 min). MTT assay was used to determine the efficacy of the treatments. Our findings in the study showed that ECT was much more successful than 5-FU treatment alone in Caco-2 colon cancer cells. Application of 4 mT ELF-MF after CT significantly increased the viability of the Caco-2 cancer cells compared to the CT group alone (p < .05). An increase in the viability of cells treated with 4 mT after ECT was observed compared to ECT alone. Similarly, there was an increase in the viability of cells treated with MF prior to ECT treatment (p < .05). The results show that exposure to ELF-MF at 4 mT flux density significantly reduces CT and ECT treatment efficacy in Caco-2 colon cancer cells.

Synthesis, characterization, antiproliferative of pyrimidine based ligand and its Ni(II) and Pd(II) complexes and effectiveness of electroporation.

In the study, a new Schiff base (ligand) was obtained using 4-aminopyrimidine-2(1H)-one, the starting material, and 2,3,4-trimethoxy benzaldehyde. Ni(II) and Pd(II) complexes were obtained from the reaction of the ligand and NiCl2·6H2O, PdCl2(CH3CN)2 (1:1 ratio). These compounds were characterized using the elemental and mass analysis, 1H, 13C-NMR, FT-IR, UV-Vis, magnetic susceptibility, thermal analysis, and the X-ray diffraction analyses. The antiproliferative activities of the synthesized ligand, Ni(II) and Pd(II) complexes were identified on the HepG2 (human liver cancer cells) cell line and their biocompatibility was tested on the L-929 (fibroblast cells) cell line by the MTT analysis method. Furthermore, the effects of electroporation (EP) on the cytotoxic activities of synthesized compounds were investigated in HepG2 cancer cells. According to the MTT findings of the study, the ligand did not exhibit an antiproliferative activity while its Ni(II) and Pd(II) complexes exhibited an antiproliferative activity. Moreover, it was observed that the antiproliferative activity of the Pd(II) complex was stronger than that of the Ni(II) complex. The combined application of EP + compounds is much more effective than the usage of the compounds alone in the treatment of HepG2 cancer cells. The EP increased the cytotoxicity of the Ni(II) and Pd(II) complexes by 1.66, and 2.54 times, respectively. It was concluded that Ni(II) and Pd(II) complexes may contribute as potential anti-cancer agents for the treatment of hepatocellular carcinoma and yield promising results in the case of being used in ECT.Communicated by Ramaswamy H. Sarma.

Effects of electroporation on anticancer activity of 5-FU and newly synthesized zinc(II) complex in chemotherapy-resistance human brain tumor cells.

Zn(II) complex of Schiff base derived from the condensation of 4-aminopyrimidine-2(1H)-one with salicylaldehyde was prepared and characterized by various physico-chemical and spectral methods for structure determination. The cytotoxic activity of the Zn(II) complex was investigated in comparison with 5-fluorouracil (5-FU) against two different human brain tumor cell lines (T98G and U118), while primer human dermal fibroblast cells (HDF) was used as control for biocompatibility. Then, the effectiveness of electroporation (EP) on cytotoxic activities of these compounds has been examined. The cytotoxicities of the 5-FU and new Zn(II) complex, alone or in combination with electroporation, were determined by MTT assay. The Zn(II) complex showed good cytotoxicity against T98G and U118 brain tumor cell lines with IC50 = 282.47 and 297.91 µM respectively, while it was safe on HDF healthy cells with IC50 = 826.72 µM. The 5-FU exhibited less cytotoxicity compared to the Zn(II) complex against T98G (IC50 = 382.35 µM) and U118 (IC50 = 396.56 µM) tumor cell lines. The combined application of Zn (II) + EP decreased the IC50 value by 5.96-fold in T98G cells and 4.76-fold in U118 cells. EP showed a similar effect in its combined application with 5-FU, resulting in a decrease of the IC50 value of 4.22-fold in the T98G cells and 3.84-fold in the U118 cells. In a conclusion, the Zn(II) complex exhibited an anticancer potential against both brain tumor cell lines (T98G and U118) and EP greatly increased the cytotoxicity of Zn(II) complex and 5-FU on these chemotherapy-resistant cells.

Effect of 900-, 1800-, and 2100-MHz radiofrequency radiation on DNA and oxidative stress in brain.

Ubiquitous and ever increasing use of mobile phones led to the growing concern about the effects of radiofrequency radiation (RFR) emitted by cell phones on biological systems. The aim of this study is to explore whether long-term RFR exposure at different frequencies affects DNA damage and oxidant-antioxidant parameters in the blood and brain tissue of rats. 28 male Sprague Dawley rats were randomly divided into four equal groups (n = 7). They were identified as Group 1: sham-control, Group 2: 900 MHz, Group 3: 1800 MHz, and Group 4: 2100 MHz. Experimental groups of rats were exposed to RFR 2 h/day for 6 months. The sham-control group of rats was subjected to the same experimental condition but generator was turned off. Specific absorption rates (SARs) at brain with 1 g average were calculated as 0.0845 W/kg, 0.04563 W/kg, and 0.03957, at 900 MHz, 1800 MHz, and 2100 MHz, respectively. Additionally, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), total antioxidant status (TAS), and total oxidant status (TOS) analyses were conducted in the brain tissue samples. Results of the study showed that DNA damage and oxidative stress indicators were found higher in the RFR exposure groups than in the sham-control group. In conclusion, 900-, 1800-, and 2100-MHz RFR emitted from mobile phones may cause oxidative damage, induce increase in lipid peroxidation, and increase oxidative DNA damage formation in the frontal lobe of the rat brain tissues. Furthermore, 2100-MHz RFR may cause formation of DNA single-strand breaks.

The Effects of Phrenic Nerve Degeneration by Axotomy and Crush on the Electrical Activities of Diaphragm Muscles of Rats.

The aim of this study was to investigate the effect of axotomy and crush-related degeneration on the electrical activities of diaphragm muscle strips of experimental rats. In the present study, twenty-one male Wistar-albino rats were used and divided into three groups. The animals in the first group were not crushed or axotomized and served as controls. Phrenic nerves of the rats in the second and third groups were crushed or axotomized in the diaphragm muscle. Resting membrane potential (RMP) was decreased significantly in both crush and axotomy of diaphragm muscle strips of experimental rats (p < 0.05). Depolarization time (T DEP) and half-repolarization (1/2 RT) time were significantly prolonged in crush and axotomy rats (p < 0.05). Crushing or axotomizing the phrenic nerves may produce electrical activities in the diaphragm muscle of the rat by depolarization time and half-repolarization time prolonged in crush and axotomy rats.