Synthesis of vitamin E and aliphatic lipid vanadium(IV) and (V) complexes, and their cytotoxic properties.

Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the ß-tocopherol derivatives with iminodiethanol (ß-tocDEA) and dipicolylamine (ß-tocDPA) as well their VV and VIV complexes, [VVO(ß-tocDEA] and [VIVO(ß-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV-Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the ß-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2'-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942-4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin.

Antitumor effects of the electromagnetic resonant frequencies derived from the 1H NMR spectrum of Ph3Sn(Mercaptonicotinic)SnPh3 complex.

The aim of this article is to investigate the potential cytotoxic and antitumor effects of the resonant electromagnetic fields (rEMFs) derived from the 1H NMR spectrum of the Ph3Sn(Mercaptonicotinic)SnPh3 complex (SnMNA). The ability of the complex's rEMFs to induce leiomyosarcoma (LMS) cell death and to recess tumor (leiomyosarcoma) development in Wistar rats was evaluated. The effects of the simultaneous administration of the SnMNA complex at extremely low concentrations and exposure to its rEMFs was also investigated. The emission of the 1H NMR spectrum of the complex alone or in a combination with low ineffective doses of the complex decreased LMS cell viability mainly through apoptosis. Moreover, the results from the in vivo experiments showed a significant prolongation of life expectancy in tumor-bearing rats exposed to the rEMFs alongside a deceleration in tumor growth rate. We speculate that the rEMFs of a biologically active substance could exert similar biological effects as the substance itself, mainly when is combined with extremely low ineffective concentrations of the substance.

Curcumin Acts as a Chemosensitizer for Leiomyosarcoma Cells In Vitro But Fails to Mediate Antioxidant Enzyme Activity in Cisplatin-Induced Experimental Nephrotoxicity in Rats.

Background. Cisplatin (cis-diamminedichloroplatinum) is a widely used chemotherapeutic agent for the treatment of various cancers. Although it represents an effective regimen, its application is accompanied by side effects to normal tissues, especially to the kidneys. Cisplatin generates free radicals and impairs the function of antioxidant enzymes. Modulation of cisplatin-induced oxidative stress by specific antioxidant molecules represents an attractive approach to minimize side effects. Methods. We studied the ability of curcumin to sensitize leiomyosarcoma (LMS) cells to cisplatin. Assays for cell proliferation, mitochondrial function, induction of apoptosis, and cell cycle arrest were performed using various concentrations of cisplatin and a concentration of curcumin that caused a nonsignificant reduction in cell viability. Moreover, the effect of curcumin was examined against cisplatin-induced experimental nephrotoxicity. Renal injury was assessed by measuring serum creatinine, blood urea nitrogen (BUN), and the kidney's relative weight. Oxidative stress was measured by means of enzymatic activities of superoxide dismutase and glutathione peroxidase in the rats' blood and malondialdehyde levels in rats' urine. Results. In our study, we found that curcumin sensitizes LMS cells to cisplatin by enhancing apoptosis and impairing mitochondrial function. In an in vivo model of cisplatin-induced experimental nephrotoxicity, intraperitoneal administration of curcumin failed to preserve blood's antioxidant enzyme activity and decrease lipid peroxidation. Nevertheless, curcumin was able to protect nephrons' histology from cisplatin's toxic effect. Conclusion. Our results showed that curcumin can act as chemosensitizer, but its role as an adjunctive cisplatin-induced oxidative stress inhibitor requires further dose-finding studies to maximize the effectiveness of chemotherapy.

Modulation of cisplatin cytotoxic activity against leiomyosarcoma cells by epigallocatechin-3-gallate.

The aim of this study was to investigate the cytotoxic effect cisplatin in combination with epigallocatechin-3-gallate (EGCG) on leiomyosarcoma cells (LMS cells) in order to identify a less toxic but equally effective alternative. Assays for cell proliferation, colony formation efficiency, induction of apoptosis and cell cycle arrest were performed using the IC50 of cisplatin (8.6 µΜ) as a reference value and a concentration of EGCG (30 µΜ) that caused a non-significant reduction in cell proliferation. Pre-treatment of cells with EGCG for 24 h before the addition of cisplatin increased cytotoxicity up to 8.5% (p < 0.05) and the number of apoptotic cells by 40%. Epigallocatechin-3-gallate failed to alter S-phase cell cycle arrest induced by cisplatin and to modulate cisplatin effects on mitochondrial function. These results indicate that pre-treatment with EGCG could be used as an adjunctive therapy to maximise effectiveness of chemotherapy.

The healing effect of four different silver complexes on full-thickness skin burns in a rat model.

AIM: This study was carried-out to investigate the effect of four different silver substances (S1, S2, S3, and S4) on burn wound healing in a rat model. MATERIALS AND METHODS: One hundred and eighty Wistar rats were used. Animals were randomized into six groups to receive no treatment (CG, control group), and local application of the solvent of silver substances (SG, solvent group), as well as of the four silver substances (EG1-EG4 groups for substances S1-S4, respectively). On days 0, 3, 6, 12, 21, and 31 following burn wound infliction, the size and healing progress of each wound were recorded and evaluated by means of clinical evaluation, planimetry and histological examination. RESULTS: According to our findings lower infection rates, as well as significantly accelerated wound healing and faster re-epithelialization were recorded in EG1, EG2, and EG4 compared to the other groups. DISCUSSION: The use of S1, S2, and S4 substances proved to be an effective treatment of burn wounds that ensured better outcomes compared to the control and solvent groups, as well as with the use of S3 substance. Nevertheless, they failed to produce short-term healing of the full-thickness burn. Further research is required to examine the possibility of speeding the treatment of full-thickness burns by these complexes in order to reduce healing time to acceptable limits and prevent the need for surgery.

Cytotoxic and anticancer effects of the triorganotin compound [(C6H5)3Sn(cmbzt)]: an in vitro, ex vivo and in vivo study.

Since the initial success of cisplatin, metal complexes and organometallic compounds have been gaining growing interest in cancer therapy. It is well known that organotin(IV) compounds display strong biological activity. The triorganotin compound [(C(6)H(5))(3)Sn(cmbzt)] (cmbzt=5-chloro-2-mercaptobenzothiazole) (SnCMB), was tested for its antiproliferative and antitumour activities. Two sets of experimental procedures were followed: (1) In vitro and ex vivo procedures included the study of the cytotoxic activity of the complex against leiomyosarcoma cells (LMS) and on a normal human fibroblast line (MRC5) by the MTT assay (cell proliferation), colony formation efficiency and flow cytometric analysis with Annexin V-FITC. The anticoagulation properties of the complex were also studied. (2) In vivo procedures included acute toxicity studies and finally administration of the complex to tumour bearing Wistar rats. The results showed that the complex exhibited potent cytotoxic activity (LMS IC(50)=155 nM) and induced significant apoptosis against LMS cells. Acute toxicity studies on Wistar rats presented kidney and liver toxicity at a single dose of 40 mg/kg body wt. Furthermore, antitumour activity studies on sarcoma bearing Wistar rats revealed that SnCMB complex, administrated in two different therapeutic schemes (treated with 4 × 2 mg/kg body wt every 5 days and 3 × 2.67 mg/kg body wt every 10 days of SnCMB complex), prolonged mean survival time (by 50% and 70% respectively), but failed to decrease the mean tumour growth rate (MTGR) compared to the control group (p<0.01). In conclusion, the organic complex SnCMB possess potent cytotoxic and antimetastatic effects, and low toxicity introducing it as possible successor of organometallic compounds used nowadays in chemotherapy.

Functionality of natural killer cells from end-stage cancer patients exposed to coherent electromagnetic fields.

The main objective of our study is to investigate whether an enhancement of the immune system in end-stage cancer patients is achieved by exposure to coherent electromagnetic fields. For this reason, 15 end-stage cancer patients were exposed at low intensity, coherent electromagnetic fields at radiofrequencies ranging from 600 kHz-729 Hz, for 8 h/day, 6 days/week for 4 weeks. NKs number and cytotoxicity of NK T-lymphocytes versus K562 cancer cell line were estimated by flow cytometry, before and after exposure. Data showed that the exposure of the end-stage cancer patients to the coherent electromagnetic fields resulted in a significant increase of the number and the cytotoxicity of the NK T-lymphocytes against cancer cells, in all patients. Exposure to coherent EMFs at radiofrequencies increases the number and cytotoxicity of NK T-lymphocytes, which may contribute to the improvement of cancer patients' status.

Effects of pulsed electromagnetic fields on benign prostate hyperplasia.

INTRODUCTION: Benign prostate hyperplasia (BPH) has been treated with various types of electromagnetic radiation methods such as transurethral needle ablation (TUNA), interstitial laser therapy (ILC), holmium laser resection (HoLRP). In the present study, the effects of a noninvasive method based on the exposure of patients with BPH to a pulsative EM Field at radiofrequencies have been investigated. MATERIALS AND METHODS: Twenty patients with BPH, aging 68-78 years old (y.o), were enrolled in the study. Patients were randomly divided into two groups: the treatment group (10 patients, 74.0 ± 5.7 y.o) treated with the α-blocker Alfusosin, 10 mg/24 h for at least 4 weeks, and the electromagnetic group (10 patients, 73.7 ± 6.3 y.o) exposed for 2 weeks in a very short wave duration, pulsed electromagnetic field at radiofrequencies generated by an ion magnetic inductor, for 30 min daily, 5 consecutive days per week. Patients of both groups were evaluated before and after drug and EMF treatment by values of total PSA and prostatic PSA fraction, acid phosphate, U/S estimation of prostate volume and urine residue, urodynamic estimation of urine flow rate, and International Prostate Symptom Score (IPSS). RESULTS: There was a statistically significant decrease before and after treatment of IPSS (P < 0.02), U/S prostate volume (P < 0.05), and urine residue (P < 0.05), as well as of mean urine flow rate (P < 0.05) in patients of the electromagnetic group, in contrast to the treatment group who had only improved IPSS (P < 0.05). There was also a significant improvement in clinical symptoms in patients of the electromagnetic group. Follow-up of the patients of this group for one year revealed that results obtained by EMFs treatment are still remaining. CONCLUSION: Pulsed electromagnetic field at radiofrequencies may benefit patients with benign prostate hyperplasia treated by a non-invasive method.

Anticancer and cytotoxic effects of a triorganotin compound with 2-mercapto-nicotinic acid in malignant cell lines and tumor bearing Wistar rats.

Nowadays, investigation for possible therapeutic applications of various metal-based drugs attracts the scientific interest worldwide. The triorganotin compound bis[triphenyltin(IV)](3-carboxy-pyridine-2-thionato) (SnMNA), was tested for its anti-proliferative and antitumor activities. Cytotoxic activity was assessed by Trypan blue and 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide assay (MTT). SnMNA exhibited potent cytotoxic effects against leiomyosarcoma cells (LMS) and human breast adenocarcinoma cells (MCF-7), which is 200 times stronger than that of cisplatin. Moreover, SnMNA induced significant apoptosis in LMS and MCF-7 cells characterized by flow cytometry analysis and DNA fragmentation. Acute and chronic toxicity studies on Wistar rats caused kidney and lung toxicity at a single dose of 80mg/kgBody Weight (BW) or four repeated doses of 8mg/kgBW once per week. Furthermore, antitumor activity studies on sarcoma bearing Wistar rats revealed that SnMNA complex at four repeated doses of 5.4mg/kgBW every three days prolonged mean survival time of the animal at 200% and decreased mean tumor growth rate (MTGR) compared to the control group (p<0.05). It is noteworthy to mention that the 30% (3 out of 10) of the bearing animals were totally cured. These findings indicate that SnMNA might be a promising new antitumor agent.

Changes in copper and zinc plasma concentrations during the normal menstrual cycle in women.

OBJECTIVE: To investigate whether there is a fluctuation of the copper and zinc plasma levels during the menstrual cycle and if this correlates to the physiological fluctuations of estradiol and progesterone plasma concentrations in eumenorrhoic women. METHODS: We studied 14 eumenorrhoic women. Copper (Cu), zinc (Zn), estradiol (E2) and progesterone (Prg) plasma concentrations, during time of menstruation (time 1), midfollicular phase (time 2), time of ovulation (time 3) and midluteal phase (time 4) were determined. RESULTS: We observed significant changes in both copper plasma concentrations and zinc plasma concentrations during the four times studied (p < 0.05). The changes of Cu during the various phases correlated negatively with the changes in E2 (r > 0.5, p < 0.05), whereas the changes of Zn correlated positively with those of E2 (r > 0.8, p < 0.05). We were unable to demonstrate any statistically significant correlation between Cu and Prg or Zn and Prg. CONCLUSIONS: This study indicates that there is a cyclic fluctuation of Cu and Zn concentrations in plasma during the menstrual cycle, in healthy eumenorrhoic women. This cyclic fluctuation might be due to the cyclic fluctuation of plasma levels of E2.

Anticancer effects on leiomyosarcoma-bearing Wistar rats after electromagnetic radiation of resonant radiofrequencies.

In the present study, the effects of a resonant low intensity static electromagnetic field (EMF), causing no thermal effects, on Wistar rats have been investigated. Sarcoma cell lines were isolated from leiomyosarcoma tumors induced in Wistar rats by the subcutaneous (s.c) injection of 3,4-benzopyrene. Furthermore, smooth muscle cells (SMC) were isolated from the aorta of Wistar rats and cultivated. Either leiomyosarcoma cells (LSC) or SMC were used to record a number of characteristic resonant radiofrequencies, in order to determine the specific electromagnetic fingerprint spectrum for each cell line. These spectra were used to compose an appropriate algorithm, which transforms the recorded radiofrequencies to emitted ones. The isolated LSC were cultured and then exposed to a resonant low intensity radiofrequency EMF (RF-EMF), at frequencies between 10 kHz to 120 kHz of the radiowave spectrum. The exposure lasted 45 consecutive minutes daily, for two consecutive days. Three months old female Wistar rats were inoculated with exposed and non-exposed to EMF LSC (4 x 10(6) LCS for animal). Inoculated with non-exposed to EMF cells animals were then randomly separated into three Groups. The first Group was sham exposed to the resonant EMF (control Group-CG), the second Group after the inoculation of LSC and appearance of a palpable tumor mass, was exposed to a non-resonant EMF radiation pattern, for 5 h per day till death of all animals (experimental control Group-ECG). The third Group of animals after inoculation of LSC and the appearance of a palpable tumor mass, was exposed to the resonant EMF radiation for 5 h per day, for a maximum of 60 days (experimental Group-I, EG-I). A fourth Group of animals was inoculated with LSC exposed to EMF irradiation and were not further exposed to irradiation (experimental Group-II, EG-II). Tumor induction was 100% in all Groups studied and all tumors were histologically identified as leiomyosarcomas. In the case of the EG-I, a number of tumors were completely regretted (final tumor induction: 66%). Both Groups of animals inoculated with exposed or non-exposed to the EMF LSC, (EG-I and EG-II, respectively) demonstrated a significant prolongation of the survival time and a lower tumor growth rate, in comparison to the control Group (CG) and the experimental control Group (ECG). However, the survival time of EG-I animals was found to be significantly longer and tumor growth rate significantly lower compared to EG-II animals. In conclusion, our results indicate a specific anticancer effect of resonant EMF irradiation. These results may possibly be attributed to (a) the duration of exposure of LSC and (b) the exposure of the entire animal to this irradiation.

Effects of low intensity static electromagnetic radiofrequency fields on leiomyosarcoma and smooth muscle cell lines.

In this study we investigated the effects of low intensity static radiofrequency electromagnetic field (EMF) causing no thermal effects, on leiomyosarcoma cells (LSC), isolated from tumors of fifteen Wistar rats induced via a 3,4-benzopyrene injection. Electromagnetic resonance frequencies measurements and exposure of cells to static EMF were performed by a device called multi channel dynamic exciter 100 V1 (MCDE). The LSC were exposed to electromagnetic resonance radiofrequencies (ERF) between 10 kHz to 120 kHz, for 45 min. During a 24h period, after the exposure of the LSC to ERF, there was no inhibition of cells proliferation. In contrast, at the end of a 48 h incubation period, LSC proliferation dramatically decreased by more than 98% (P<0.001). At that time, the survived LSC were only 2% of the total cell population exposed to ERF, and under the same culture conditions showed significant decrease of proliferation. These cells were exposed once again to ERF for 45 min (totally 4 sessions of exposure, of 45 min duration each) and tested using a flow cytometer. Experiments as above were repeated five times. It was found that 45% of these double exposed to ERF, LSC (EMF cells) were apoptotic and only a small percentage 2%, underwent mitosis. In order to determinate their metastatic potential, these EMF cells were also counted and tested by an aggregometer for their ability to aggregate platelets and found to maintain this ability., since they showed no difference in platelet aggregation ability compared to the LSC not exposed to ERF (control cells). In conclusion, exposure of LSC to specific ERF, decreases their proliferation rate and induces cell apoptosis. Also, the LSC that survived after exposed to ERF, had a lower proliferation rate compared to the LSC controls (P<0.05) but did not loose their potential for metastases (platelet aggregation ability). The non-malignant SMC were not affected by the EMF exposure (P<0.4). The specific ERF generated from the MCDE electronic device, used in this study, is safe for humans and animals, according to the international safety standards.

Antioxidant protection during the menstrual cycle: the effects of estradiol on ascorbic-dehydroascorbic acid plasma levels and total antioxidant plasma status in eumenorrhoic women during the menstrual cycle.

BACKGROUND: Estrogens, apart from their classic role as steroid hormones, also possess significant antioxidant properties. The present study was undertaken to assess the antioxidant potential of the female during the various menstrual phases and to investigate the correlation between ascorbic acid, dehydroascorbic acid plasma levels, total antioxidant plasma status, and estradiol levels. DESIGN AND METHODS: Thirteen eumenorrhoic women were studied. Ascorbic acid and dehydroascorbic acid plasma levels, total antioxidant plasma status, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone during time of menstruation, midfollicular phase, time of ovulation, and midluteal phase were determined. Ascorbic-dehydroascorbic acid ratio was also calculated. RESULTS: A progressive significant rise in ascorbic acid plasma levels (p < 0.01), ascorbic-dehydroascorbic acid ratio (p < 0.001), and total antioxidant plasma status (p < 0.05) from menstruation to ovulation was observed. Moreover, a significant decrease in dehydroascorbic acid was found at the same phases (p < 0.05). Changes of estradiol levels during the menstrual cycle correlated positively with the changes of ascorbic acid levels and total antioxidant plasma status (p < 0.05). Furthermore, estradiol levels correlated positively with ascorbic acid levels (p < 0.05, r < 0.5), ascorbic-dehydroascorbic acid ratio (p < 0.05, r < 0.5), and total antioxidant plasma status (p < 0.05, r < 0.8) in all menstrual phases. CONCLUSIONS: An elevated antioxidant protection during ovulation and the midluteal phase appears to be present in eumenorrhoic women. Moreover we observed a cyclic variation in the antioxidant parameters we assayed in the females in the present study, which could be due to cyclic changes in estradiol levels.