Ruthenium (II)/allopurinol complex inhibits breast cancer progression via multiple targets.

Metal complexes based on ruthenium have established excellent activity with less toxicity and great selectivity for tumor cells. This study aims to assess the anticancer potential of ruthenium(II)/allopurinol complexes called [RuCl2(allo)2(PPh3)2] (1) and [RuCl2(allo)2(dppb)] (2), where allo means allopurinol, PPh3 is triphenylphosphine and dppb, 1,4-bis(diphenylphosphino)butane. The complexes were synthesized and characterized by elemental analysis, IR, UV-Vis and NMR spectroscopies, cyclic voltammetry, molar conductance measurements, as well as the X-ray crystallographic analysis of complex 2. The antitumor effects of compounds were determined by cytotoxic activity and cellular and molecular responses to cell death mechanisms. Complex 2 showed good antitumor profile prospects because in addition to its cytotoxicity, it causes cell cycle arrest, induction of DNA damage, morphological and biochemical alterations in the cells. Moreover, complex 2 induces cell death by p53-mediated apoptosis, caspase activation, increased Beclin-1 levels and decreased ROS levels. Therefore, complex 2 can be considered a suitable compound in antitumor treatment due to its cytotoxic mechanism.

Noninvasive intratumoral thermal dose determination during in vivo magnetic nanoparticle hyperthermia: combining surface temperature measurements and computer simulations.

PURPOSE: Noninvasive thermometry during magnetic nanoparticle hyperthermia (MNH) remains a challenge. Our pilot study proposes a methodology to determine the noninvasive intratumoral thermal dose during MNH in the subcutaneous tumor model. METHODS: Two groups of Ehrlich bearing-mice with solid and subcutaneous carcinoma, a control group (n = 6), and a MNH treated group (n = 4) were investigated. Histopathology was used to evaluate the percentage of non-viable lesions in the tumor. MNH was performed at 301 kHz and 17.5 kA.m-1, using a multifunctional nanocarrier. Surface temperature measurements were obtained using an infrared camera, where an ROI with 750 pixels was used for comparison with computer simulations. Realistic simulations of the bioheat equation were obtained by combining histopathology intratumoral lesion information and surface temperature agreement of at least 50% of the pixel's temperature data calculated and measured at the surface. RESULTS: One animal of the MNH group showed tumor recurrence, while two others showed complete tumor remission (monitored for 585 days). Sensitivity analysis of the simulation parameters indicated low tumor blood perfusion. Numerical simulations indicated, for the animals with complete remission, an irreversible tissue injury of 91 ± 5% and 100%, while the one with recurrence had a lower value, 56 ± 7%. The computer simulations also revealed the in vivo heat efficiency of the nanocarrier. CONCLUSION: A new methodology for determining noninvasively the three-dimensional intratumoral thermal dose during MNH was developed. The method demonstrates the potential for predicting the long-term preclinical outcome of animals treated with MNH.

Real-time infrared thermography detection of magnetic nanoparticle hyperthermia in a murine model under a non-uniform field configuration.

PURPOSE: Magnetic nanoparticle hyperthermia consists of an increase of the temperature of magnetic nanoparticles (heat centres) due to the interaction of their magnetic moments with an alternating magnetic field. In vivo experiments using this method usually use a few fibre-optic thermometers inserted in the animal body to monitor the heat deposition. As a consequence, only a few points of the 3D temperature distribution can be monitored by this invasive procedure. It is the purpose of this work to show that non-invasive infrared thermography is able to detect, in real time, magnetic nanoparticle hyperthermia as well as monitor the harmful field-induced eddy currents in a murine model with a subcutaneous tumour. This surface temperature measurement method has the potential to give information about the intratumoral temperature. MATERIALS AND METHODS: The non-invasive magnetic hyperthermia experiments were performed at 300 kHz in non-uniform field configuration conditions in healthy mice and murine tumour induced by sarcoma S180. A soft ferrite-based biocompatible magnetic colloid consisting of manganese-ferrite nanoparticles surface-coated with citric acid were used in the experiments, which were extensively characterised by several techniques (transmission electron microscopy (TEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM)). The amplitude of the alternating magnetic fields was obtained from measurements using an AC field probe at similar experimental conditions. The temperature measurements were obtained from an infrared thermal camera and a fibre-optic thermometer. RESULTS: Three-minute magnetic hyperthermia experiments revealed surface temperature increase as high as 11 °K in healthy and (5 °K in S180 tumour) animals when injecting subcutaneously 2 mg of magnetic nanoparticles (86 µL of magnetic fluid), in contrast to around 1.5 °K (for healthy) and 2.5 °K (for cancerous) animals in experiments without the colloid due to field-induced eddy currents at the animal surface. The thermographic temperature measurements were found to agree with the fibre-optic measurements within a 5% error, and were associated with the skin emissivity angle of dependence in the experimental set-up. On the other hand, a 30-min magnetic nanoparticle hyperthermia revealed surface temperature increases as high as 12 °K close to the injection site, while above 2-3 cm no significant temperature increase was observed. Curiously, the intratumoral temperature, monitored by a fibre-optic sensor, was found to be almost the same as the thermal camera surface temperature after achieving an equilibrium temperature regime. From the observed isotherms at the animal surface, using an analytical heat conduction model, taking into account surface conductance, we estimate a magnetic heating power of 0.45 W/cm(3) and a specific loss power (SLP) of 85 W/g for a field of the order of only 10 kA/m at the injection site region. CONCLUSIONS: The results indicate that infrared thermography may be a promising tool for both early cancer detection and for hyperthermia treatment (at least for subcutaneous tumours), since the method permits access to information about the intratumoral temperature during a real-time magnetic hyperthermia as well as to estimate the in vivo nanoparticles SLP.

Antitumor effects of snake venom chemically modified Lys49 phospholipase A2-like BthTX-I and a synthetic peptide derived from its C-terminal region.

The present work evaluates both in vitro and in vivo antitumor activity of BPB-modified BthTX-I and its cationic synthetic peptide derived from the 115-129 C-terminal region. BPB-BthTX-I presented cytotoxicity of 10-40% on different tumor cell lines, which were also susceptible to the lytic action of the synthetic peptide. Injection of the modified protein or the peptide in mice, 5 days after transplantation of S180 tumor cells, reduced 30 and 36% of the tumor size on day 14th and 76 and 79% on day 60th, respectively, when compared to the untreated control group. Thus, these antitumor properties might be of interest in the development of therapeutic strategies against cancer.

In vitro cytotoxicity and in vivo zebrafish toxicity evaluation of Ru(ii)/2-mercaptopyrimidine complexes.

In this paper, four new ruthenium complexes, [Ru(N-S)(dppm)2]PF6 (1), [Ru(N-S)(dppe)2]PF6 (2), [Ru(N-S)2(dppp)] (3) and [Ru(N-S)2(PPh3)2] (4) [dppm = 1,1-bis(diphenylphosphino)methane, dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, PPh3 = triphenylphosphine and N-S = 2-mercaptopyrimidine anion] were synthesized and characterized using spectroscopy techniques, molar conductance, elemental analysis, electrochemical techniques and X-ray diffraction. The DNA binding studies were investigated using voltammetry and spectroscopy techniques. The results show that all complexes exhibit a weak interaction with DNA. HSA interaction with the complexes was studied using fluorescence emission spectroscopy, where the results indicate a spontaneous interaction between the species by a static quenching mechanism. The cytotoxicity of the complexes was evaluated against A549, MDA-MB-231 and HaCat cells by MTT assay. Complexes (1) and (2), which are very active against triple negative MDA-MB-231, were subjected to further biological tests with this cell line. The cytotoxic activity triggered by the complexes was confirmed by clonogenic assay. Cell cycle analyses demonstrated marked anti-proliferative effects, especially at the G0/G1 and S phases. The morphological detection of apoptosis and necrosis - HO/PI and Annexin V-FITC/PI assay, elucidated that the type of cell death triggered by these complexes was probably by apoptosis. The in vivo toxicological assessment performed on zebrafish embryos revealed that complexes (1) and (2) did not present embryotoxic or toxic effects during embryonic and larval development showing that they are promising new prototypes of safer and more effective drugs for triple negative breast cancer treatment.

High Species C Human Adenovirus Genome Copy Numbers in the Treated Water Supply of a Neotropical Area of the Central-West Region of Brazil.

There is little information about the presence of human adenovirus (HAdV) in drinking water in Neotropical regions. Thus, the present study sought to conduct quantification and molecular characterization of HAdVs detected in treated water samples from an area of the Cerrado ecoregion of Brazil. Between August and November 2012, samples were collected from four treated water reservoirs and their respective sites along the water distribution network of the city of Goiânia, for a total of 80 samples. All samples were concentrated and analyzed by qPCR, and selected samples were sequenced. Overall, 76.6 (10(0)-10(9) GC mL(-1)) and 37.5% (10(1)-10(8) GC mL(-1)) of samples drawn from reservoirs and their distribution sites, respectively, were positive for virus by qPCR. All samples selected for sequencing were characterized as species C human adenovirus. Such high HAdV counts have in treated water samples. This finding merits special attention, particularly from the sanitation authorities, because the high number of GC mL(-1) may be an indicative of risk to human health.

Proteomic profile response of Paracoccidioides lutzii to the antifungal argentilactone.

The dimorphic fungi Paracoccidioides spp. are the etiological agents of paracoccidioidomycosis (PCM), a mycosis of high incidence in Brazil. The toxicity of drug treatment and the emergence of resistant organisms have led to research for new candidates for drugs. In this study, we demonstrate that the natural product argentilactone was not cytotoxic or genotoxic to MRC5 cells at the IC50 concentration to the fungus. We also verified the proteomic profile of Paracoccidioides lutzii after incubation with argentilactone using a label free quantitative proteome nanoUPLC-MS(E). The results of this study indicated that the fungus has a global metabolic adaptation in the presence of argentilactone. Enzymes of important pathways, such as glycolysis, the Krebs cycle and the glyoxylate cycle, were repressed, which drove the metabolism to the methylcytrate cycle and beta-oxidation. Proteins involved in cell rescue, defense and stress response were induced. In this study, alternative metabolic pathways adopted by the fungi were elucidated, helping to elucidate the course of action of the compound studied.

Atypical fluoroquinolone gold(III) chelates as potential anticancer agents: relevance of DNA and protein interactions for their mechanism of action.

Quinolones are known for their antimicrobial and antitumor activities. Gold(III) compounds constitute an emerging class of biologically active substances, of special interest as potential anticancer agents. In this work three gold(III) complexes of the fluoroquinolones antimicrobial agents norfloxacin (NOR), levofloxacin (LEVO) and sparfloxacin (SPAR) were prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, NOR, LEVO and SPAR act as bidentate neutral ligands bound to gold(III) through the nitrogen atoms of the piperazine ring, which is an unusual mode of coordination for this class of compounds. Two chloride ions occupy the remaining coordination sites. The cytotoxic activity of the fluoroquinolones and their gold(III) complexes was tested against the A20 (murine lymphoma), B16-F10 (murine melanoma) and K562 (human myeloid leukemia) tumor cell lines as well as the L919 (murine lung fibroblasts) and MCR-5 (human lung fibroblasts) normal cells lines. All complexes were more active than their corresponding free ligands. Complex [AuCl(2)(LEVO)]Cl was selected for DNA fragmentation and cell cycle analysis. Spectroscopic titration with calf-thymus DNA (CT DNA) showed that the complexes can bind weakly to CT DNA, probably by an external contact (electrostatic or groove binding). The complexes exhibit good binding propensity to bovine serum albumin (BSA) having relatively high binding constant values.

Siolmatra brasiliensis (Cogn.) Baill., Cucurbitaceae, acute toxicity in mice / Toxicidade aguda de Siolmatra brasiliensis (Cogn.) Baill., Cucurbitaceae, em camundongos

Siolmatra brasiliensis (Cogn.) Baill., Cucurbitaceae, commonly known as "pluméria" or "taiuiá", is widely used in different ways in Brazilian popular medicine to treat several diseases. Acute toxicity of Siolmatra brasiliensis crude ethanolic extract (CEE) was investigated in mice. No mortality or signs of CEE toxicity were observed at the doses of 10 and 100 mg/kg bw, but the administration of 1000 and 2000 mg/kg bw caused several adverse behavioral effects and mortality. Macroscopic inspection of the organs showed morphologic alterations in the heart of animals treated with doses of 1000 and 2000 mg/kg bw. According to our results, S. brasiliensis CEE has an LD50 of 1000 mg/kg bw. We conclude that S. brasiliensis CEE was safe at the doses of 10 and 100 mg/kg bw and presented toxicity at the doses of 1000 and 2000 mg/kg bw.

Siolmatra brasiliensis (Cogn.) Baill., Cucurbitaceae, popularmente conhecida como "pluméria" ou "taiuiá" é utilizada na medicina popular brasileira para diversos fins terapêuticos. O estudo de toxicidade aguda do extrato bruto etanólico (EBE) de Siolmatra brasiliensis foi investigado em camundongos. Nenhuma mortalidade ou sinais de toxicidade foram observados nas doses de 10 e 100 mg/kg, entretanto em doses administradas de 1000 e 2000 mg/kg levou as diversas alterações comportamentais e mortalidade. A DL50 para o EBE foi de 1000 mg/kg. Análise macroscópica dos órgãos demonstrou alterações morfológicas no coração dos animais tratados com 1000 e 2000 mg/kg. Por meios destes resultados conclui-se que o EBE de Siolmatra brasiliensis é seguro em doses de 10 and 100 mg/kg e apresentou toxicidade nas doses de 1000 e 2000 mg/kg.