Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents.

Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers.

1T-Phase Dirac Semimetal PdTe2 Nanoparticles for Efficient Photothermal Therapy in the NIR-II Biowindow.

1T-phase transition-metal dichalcogenides (TMDs) nanomaterials are one type of emerging and promising near-infrared II (NIR-II) photothermal agents (PTAs) derived from their distinct metallic electronic structure, but it is still challenging to synthesize these nanomaterials. Herein, PdTe2 nanoparticles (PTNs) with a 1T crystal symmetry and around 50 nm in size are prepared by an electrochemical exfoliation method, and the corresponding photothermal performances irradiated under a NIR-II laser have been explored. The encapsulation of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) endows PTNs with water solubility, enhanced photothermal stability, and high biocompatibility. Notably, PTN/DSPE-PEG displays a potent absorbance through the NIR-II zone and considerable photothermal conversion efficiency, which is up to 68% when irradiated with a 1060 nm laser. With these unique photothermal properties, excellent in vitro and in vivo tumor inhibition effects of PTN/DSPE-PEG have been achieved under the irradiation of a NIR-II (1060 nm) laser without visible toxicity to normal tissues, suggesting that it is an efficient NIR-II photothermal nanoagent.

preADMET analysis and clinical aspects of dogs treated with the Organotellurium compound RF07: A possible control for canine visceral leishmaniasis?

Tellurium compounds have been described as potential leishmanicides, bearing promising leishmanicidal and antimalarial effects. Therefore, the present study investigated the pharmacological potential of the organotellurane compound RF07 through preADMET parameters, such as absorption, distribution, metabolism and excretion. After studying the pharmacokinetic properties of RF07, studies were carried out on dogs naturally infected with visceral leishmaniasis after the administration of RF07, in order to assess pathophysiological parameters. Thus, dogs were divided into 4 groups with administration of daily intraperitoneal injections for 3 weeks (containing RF07 or placebo). During the trial, hematological parameters, renal and hepatic toxicity were evaluated. Serum urea, creatinine, alkaline phosphatase, transaminases (GOT and GPT), as well as hemogram results, were evaluated before the first administration and during the second and third weeks after the start of the treatment. In dogs with VL, RF07 improved liver damage, regulated GPT levels and significantly decreased leukocyte count, promoting its regularization. These phenomena occurred at the end of the third week of treatment. The administration of RF07 promoted a significant decrease in the average levels of GOT and GPT after the third week of treatment and did not significantly alter the hematological parameters. The application of RF07 in the treatment of visceral leishmaniasis suggests that it is an alternative to the disease, since the reversal of clinical signs in dogs with VL requires the use of 0.6 mg/kg.

Ammonium Fluoride Passivation of CdZnTeSe Sensors for Applications in Nuclear Detection and Medical Imaging.

Cadmium zinc telluride selenide (Cd1-xZnxTe1-ySey or CZTS) is one of the emerging CdTe-based semiconductor materials for detecting X- and gamma-ray radiation at or near room temperature (i.e., without cryogenic cooling). Potential applications of CZTS sensors include medical imaging, X-ray detection, and gamma-ray spectroscopy. Chemical passivation of CZTS is needed to reduce the conductivity of Te-rich surfaces, which reduces the noise and improves the device performance. In this study, we focus on the effect of surface passivation of CZTS using a 10% aqueous solution of ammonium fluoride. The effects of the chemical treatment were studied on the leakage current, charge transport measured as the electron mobility-lifetime (µτ) product, and the spectral resolution measured as the full-width at half-maximum (FWHM) of specific peaks. After passivation, the leakage current increased and began to decrease towards pre-passivation levels. The energy resolutions were recorded for eight applied voltages between -35 V and -200 V. The results showed an average of 25% improvement in the detector's energy resolution for the 59.6 keV gamma peak of Am-241. The electron µτ product was unchanged at 2 × 10-3 cm2/V. These results show that ammonium fluoride is effective for chemical passivation of CZTS detectors.

The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers.

Cancer therapies are associated with increased infertility risk due to accelerated reproductive aging. Oxidative stress (OS) is a potential mechanism behind ovarian toxicity by cyclophosphamide (CPM), the most ovotoxic anticancer drug. An important sensor of OS is SIRT1, a NAD+-dependent deacetylase which regulates cellular defence and cell fate. This study investigated whether the natural carotenoid crocetin and the synthetic compound AS101 protect the ovary against CPM by modulating SIRT1 and mitochondrial markers. We found that the number of primordial follicles of female CD1 mice receiving crocetin plus CPM increased when compared with CPM alone and similar to AS101, whose protective effects are known. SIRT1 increased in CPM mouse ovaries revealing the occurrence of OS. Similarly, mitochondrial SIRT3 rose, whilst SOD2 and the mitochondrial biogenesis activator PGC1-α decreased, suggesting the occurrence of mitochondrial damage. Crocetin and AS101 administration prevented SIRT1 burst suggesting that preservation of redox balance can help the ovary to counteract ovarian damage by CPM. Decreased SIRT3 and increased SOD2 and PGC1-α in mice receiving crocetin or AS101 prior to CPM provide evidence for mitochondrial protection. Present results improve the knowledge of ovarian damage by CPM and may help to develop interventions for preserving fertility in cancer patients.

Telluric Acid Ameliorates Endotoxemic Kidney Injury in Mice: Involvement of TLR4, Nrf2, and PI3K/Akt Signaling Pathways.

Being one of the most abundant trace elements in the human body, the therapeutic potential of tellurium-based compounds has been a target of interest. Recent reports denoted their redox-modulating and anti-inflammatory activities in experimental endotoxemia. However, their potential nephroprotective effect against endotoxemic kidney injury is yet to be elucidated. This study investigated the possible renoprotective effect of telluric acid (TEL) against lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice, targeting toll-like receptor 4 (TLR4), phosphoinositide 3-kinase (PI3K)/Akt, and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways as possible mechanistic contributors to TEL's effect. AKI was induced by LPS (2 mg/kg). TEL (60 µg/kg; i.p.) was administered once daily for seven consecutive days before LPS injection. Pretreatment with TEL alleviated LPS-induced AKI as evidenced by the hampered serum levels of creatinine and cystatin C. TEL also opposed LPS-induced elevation in renal kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, nuclear factor-kappa B p65, interleukin-1ß, and thiobarbituric acid-reactive substance contents. This was accompanied by a replenishment of renal glutathione, transcriptional upregulation of Nrf2, enhancement of heme oxygenase-1 activity, and a marked upregulation of phospho-PI3K and phospho-Akt protein expressions. Histopathological findings corroborated with the amendment of biochemical parameters. In view of these findings, we may conclude that TEL pretreatment purveyed novel nephroprotective effects against endotoxemic kidney injury, which might be partly attributed to the modulation of TLR4, PI3K/Akt, and Nrf2 signaling pathways and may hence provide a valuable asset for the management of endotoxemic renal complications.

Tracing Tellurium and Its Nanostructures in Biology.

Tellurium (Te) is a semimetal rare element in nature. Together with oxygen, sulfur (S), and selenium (Se), Te is considered a member of chalcogen group. Over recent decades, Te applications continued to emerge in different fields including metallurgy, glass industry, electronics, and applied chemical industries. Along these lines, Te has recently attracted research attention in various fields. Though Te exists in biologic organisms such as microbes, yeast, and human body, its importance and role and some of its potential implications have long been ignored. Some promising applications of Te using its inorganic and organic derivatives including novel Te nanostructures are being introduced. Before discovery and straightforward availability of antibiotics, Te had considered and had been used as an antibacterial element. Antilishmaniasis, antiinflammatory, antiatherosclerotic, and immuno-modulating properties of Te have been described for many years, while the innovative applications of Te have started to emerge along with nanotechnological advances over the recent years. Te quantum dots (QDs) and related nanostructures have proposed novel applications in the biological detection systems such as biosensors. In addition, Te nanostructures are used in labeling, imaging, and targeted drug delivery systems and are tested for antibacterial or antifungal properties. In addition, Te nanoparticles show novel lipid-lowering, antioxidant, and free radical scavenging properties. This review presents an overview on the novel forms of Te, their potential applications, as well as related toxicity profiles.

Dados Preliminares do Valor Prognóstico de um Novo Protocolo deCintilografia Miocárdica Ultrarrápido e com Menos Radiação emGamacâmara CZT / Preliminary Data on the Prognostic Value of a New Protocol of Ultra-fast Myocardial Scintigraphy with Less Radiation in CZT Gamma Camera

A cintilografia miocárdica de perfusão (CMP) é um dos métodos mais utilizados na avaliação de pacientes com suspeita de coronariopatia por seu valor diagnóstico e prognóstico. Duas de suas maiores limitações são o uso de radiação e a duração prolongada dosexames. Entretanto, novas Gamacâmaras de CZT (GC-CZT) têm permitido reduzir as doses dos radiotraçadores empregadas e o tempo de aquisição. O valor prognóstico desses novos protocolos não é conhecido.Objetivo: Determinar o valor prognóstico de um novo protocolo de CMP ultrarrápido e de baixa radiação numa GC-CZT. População: Pacientes com suspeita de coronariopatia consecutivamente submetidos a CMP numa GC-CZT no período de novembro de 2011 a junho de 2012.Metodologia: Foi utilizado protocolo de mesmo dia, iniciado pela fase de repouso com dose de 5 mCi e posterior estresse com dose de 15 mCi de Tc-99m sestamibi. Os tempos de aquisição foram de 6 e 3 minutos, respectivamente. Os exames foram classificados como normais ou anormais e escores de perfusão (SSS, SRS e SDS) foram calculados. Pacientes foram acompanhados mediante contato telefônico semestral. Os eventos avaliados foram morte, infarto não fatal e revascularização tardia (> 60 dias após CMP). Foi utilizado método de Coxpara identificar os preditores.Resultados: Setecentos e noventa e dois pacientes foram acompanhados por 21,3 ± 3,7 meses. A idade média foi de 65,2 ± 12,7 anos, sendo 50,3% do sexo masculino e o IMC médio de 26,9 ± 4,7. Hipertensão arterial foi o fator de risco mais frequente (59,5%), seguidode dislipidemia (51,9%) e diabetes (23,3%). Estresse físico foi empregado em 438 (55,3%) pacientes; 618 (78%) CMP foram normais. A dosimetria média dos exames foi 6 mSv e a duração média, de 48 ± 11 minutos. Durante o seguimentos ocorreram 12 óbitos, 4 infartos não fatais...

Myocardial perfusion scintigraphy (MPS) is one of the most used imaging methods for the evaluation of patients for coronary artery disease (CAD) due to its diagnostic and prognostic value. Two of its main limitations are radiation use and scan duration. However, CZT cameras (CZT-C) have allowed tracer dose and scan time reductions. However, the prognostic value of these new protocols is not known. Objective: To determine the prognostic value of a new, ultrafast, low dose protocol in a CZT-C. Population: Patients with suspect CAD undergoing MPS from 11/2011 to 6/2012 were studied. Methods: They had a 1-day Tc-99m sestamibi protocol starting with rest study (5 mCi dose) followed by stress (15 mCi). Acquisition times were 6 and 3 minutes respectively. MPS studied were classified as normal or abnormal and perfusion scores (SSS, SRS and SDS) were calculated. Patients were accompanied by 6-month phone calls. Events were defined as death, nonfatal myocardial infarction and late revascularization (> 60 days after MPS) and analyzed with the Cox method.Results: 792 patients were followed for 21.3 ± 3.7 months. Age was 65.2 ± 12.7 years, 50.3% were male and body mass index was 26.9 ± 4.7. Hypertension was the most frequent risk factor (59.5%), followed by hypercholesterolemia (51.9%) and diabetes (23.3%). Exercise was used in 438 (55.3%); 618 (78%) MPS studies were normal. Mean dosimetry was 6 mSv and mean scan time, 48 ± 11 minutes. During follow-up, there were 12 deaths...

The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes.

The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.

The organotelluride catalyst (PHTE)2NQ prevents HOCl-induced systemic sclerosis in mouse.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by skin and visceral fibrosis, microvascular damage, and autoimmunity. HOCl-induced mouse SSc is a murine model that mimics the main features of the human disease, especially the activation and hyperproliferation rate of skin fibroblasts. We demonstrate here the efficiency of a tellurium-based catalyst 2,3-bis(phenyltellanyl)naphthoquinone ((PHTE)(2)NQ) in the treatment of murine SSc, through its selective cytotoxic effects on activated SSc skin fibroblasts. SSc mice treated with (PHTE)(2)NQ displayed a significant decrease in lung and skin fibrosis and in alpha-smooth muscle actin (α-SMA) expression in the skin compared with untreated mouse SSc animals. Serum concentrations of advanced oxidation protein products, nitrate, and anti-DNA topoisomerase I autoantibodies were increased in SSc mice, but were significantly reduced in SSc mice treated with (PHTE)(2)NQ. To assess the mechanism of action of (PHTE)(2)NQ, the cytotoxic effect of (PHTE)(2)NQ was compared in normal fibroblasts and in mouse SSc skin fibroblasts. ROS production is higher in mouse SSc fibroblasts than in normal fibroblasts, and was still increased by (PHTE)(2)NQ to reach a lethal threshold and kill mouse SSc fibroblasts. Therefore, the effectiveness of (PHTE)(2)NQ in the treatment of mouse SSc seems to be linked to the selective pro-oxidative and cytotoxic effects of (PHTE)(2)NQ on hyperproliferative fibroblasts.

Selenium- and tellurium-containing multifunctional redox agents as biochemical redox modulators with selective cytotoxicity.

Various human diseases, including different types of cancer, are associated with a disturbed intracellular redox balance and oxidative stress (OS). The past decade has witnessed the emergence of redox-modulating compounds able to utilize such pre-existing disturbances in the redox state of sick cells for therapeutic advantage. Selenium- and tellurium-based agents turn the oxidizing redox environment present in certain cancer cells into a lethal cocktail of reactive species that push these cells over a critical redox threshold and ultimately kill them through apoptosis. This kind of toxicity is highly selective: normal, healthy cells remain largely unaffected, since changes to their naturally low levels of oxidizing species produce little effect. To further improve selectivity, multifunctional sensor/effector agents are now required that recognize the biochemical signature of OS in target cells. The synthesis of such compounds provides interesting challenges for chemistry in the future.

Treatment of human cancer cells with selenite or tellurite in combination with auranofin enhances cell death due to redox shift.

Selenium is an essential trace element incorporated as selenocysteine in 25 human selenoproteins. Among them are thioredoxin reductases (TrxR) and glutathione peroxidases, all central proteins in the regulation of the cellular thiol redox state. In this paper the effects of selenite and tellurite treatment in human cancer cells are reported and compared. Our results show that both selenite and tellurite, at relatively low concentrations, are able to increase the expression of mitochondrial and cytosolic TrxR in cisplatin-sensitive (2008) and -resistant (C13*) phenotypes. We further investigated the cellular effects induced by selenite or tellurite in combination with the specific TrxR inhibitor auranofin. Selenite pretreatment induced a dramatic increase in auranofin cytotoxicity in both resistant and sensitive cells. Investigation of TrxR activity and expression levels as well as the cellular redox state demonstrated the involvement of TrxR inhibition and redox changes in selenite and auranofin combined action.

Differential effect of the immunomodulator AS101 on B7-1 and B7-2 costimulatory molecules: role in the antitumoral effects of AS101.

The CD28 receptor on T cells with its ligand B7, representing the best characterized example of costimulation, has recently been demonstrated to interact with two different ligands: B7-1 and B7-2. AS101 (ammonium trichloro[dioxoethylene-O,O']tellurate), a synthetic immunomodulator with minimal toxicity, was previously shown to stimulate both mouse and human cells to proliferate and secrete a variety of cytokines. We recently found that treatment of advanced cancer patients or tumor-bearing mice with AS101 results in a clear predominance of Th1 responses with a concomitant decrease in Th2 response. Our present study demonstrates that AS101 differentially affects B7-1 and B7-2 molecule expression on mouse macrophages: it up-regulates B7-1 expression in a dose-dependent manner without affecting B7-2 expression, which leads to a profound macrophage costimulatory activity of purified T cells with soluble anti-CD3. Our results also demonstrate the differential inhibitory effect of IL-10 on T cell activation in the presence of AS101-stimulated accessory cells (AC). We show that when stimulated with AS101, AC-dependent T cell activation was more resistant to inhibition by IL-10 compared with AC stimulated by LPS. This was due to the partial resistance of AS101-stimulated macrophages to the down-regulation of B7-1 expression by IL-10. In vivo studies with AS101-treated tumor-bearing mice revealed that the predominance in Thl responses--marked by an increase in IFN-gamma and a decrease in IL-4--may be associated in part with the ability of AS101 to up-regulate B7-1 expression, which is also related to its antitumoral effects. These results suggest that AS101 may be clinically effective in conditions involving dysfunctional cytokine production.

A new immunomodulating compound (AS-101) with potential therapeutic application.

There has been interest in the potential of synthetic compounds to modify immune responses by imitation of cytokine action. Direct administration of interleukin 2 (IL-2) in conjunction with adoptive transfer of lymphokine activated killer cells has been used in the treatment of cancer, but there are toxic effects resulting from the high doses of IL-2 required. We have developed a new synthetic compound, ammonium tri-chloro(dioxoethylene-O,O'-)tellurate (AS-101), which has immunomodulating properties and minimal toxicity. The effects of AS-101 on the activation and function of immunocompetent cells have been assessed. We have found that AS-101 induces proliferation and IL-2 production by human lymphocytes in vitro, and enhances the production of IL-2 and colony-stimulating factor by mouse spleen cells. Splenocytes of BALB/c mice injected with AS-101 increased production of IL-2 and CSF in vitro in the presence of mitogen. Mononuclear cells of normal donors acquired responsiveness to recombinant IL-2 and bound monoclonal antibody to IL-2 receptor after incubation with AS-101. Splenocytes of mice treated in vivo with AS-101 expressed high levels of IL-2 receptor. The stimulation of lymphocytes by AS-101 apparently involves an increase in intracellular free calcium. AS-101 administered systemically to mice mediated antitumour effects which could be attributable to its immunomodulatory properties. In addition, AS-101 could directly enhance the ratio of OKT4 to OKT8-positive cells in cultured mononuclear cells from AIDS (acquired immune deficiency syndrome) patients. These results indicate that AS-101 is potentially useful in the treatment of clinical conditions involving immunosuppression.

Astatine-211--tellurium radiocolloid cures experimental malignant ascites.

An investigation of the efficacy of astatine-211--tellurium colloid for the treatment of experimental malignant ascites in mice reveals that this alpha-emitting radiocolloid can be curative without causing undue toxicity to normal tissue. By comparison, negatron-emitting phosphorus-32 as colloidal chromic phosphate had no antineoplastic activity. The most compelling explanation for this striking difference is the dense ionization and short range of action associated with alpha-emission. These results have important implications for the development and use of alpha-emitters as radiocolloid therapy for the treatment of human tumors.