Exploiting Unique Alignment of Cobalt Ferrite Nanoparticles, Mild Hyperthermia, and Controlled Intrinsic Cobalt Toxicity for Cancer Therapy.

Nanoparticle-based magnetic hyperthermia is a well-known thermal therapy platform studied to treat solid tumors, but its use for monotherapy is limited due to incomplete tumor eradication at hyperthermia temperature (45 °C). It is often combined with chemotherapy for obtaining a more effective therapeutic outcome. Cubic-shaped cobalt ferrite nanoparticles (Co-Fe NCs) serve as magnetic hyperthermia agents and as a cytotoxic agent due to the known cobalt ion toxicity, allowing the achievement of both heat and cytotoxic effects from a single platform. In addition to this advantage, Co-Fe NCs have the unique ability to form growing chains under an alternating magnetic field (AMF). This unique chain formation, along with the mild hyperthermia and intrinsic cobalt toxicity, leads to complete tumor regression and improved overall survival in an in vivo murine xenograft model, all under clinically approved AMF conditions. Numerical calculations identify magnetic anisotropy as the main Co-Fe NCs' feature to generate such chain formations. This novel combination therapy can improve the effects of magnetic hyperthermia, inaugurating investigation of mechanical behaviors of nanoparticles under AMF, as a new avenue for cancer therapy.

In vitro evaluation of human myoblast function after exposure to cobalt and chromium ions.

The replacement of a native hip joint by a metal-on-metal prosthesis may induce deleterious inflammatory side effects that are associated with the release of wear particles and metal ions. These events are referred to the adverse reaction to metal debris (ARMD) and the adverse local tissue reaction (ALTR). While wear particles seem involved in ARMD, the role of metal ions in ALTR and their impact on myoblasts, located in the prosthesis vicinity, has not been fully identified. To clarify this issue we investigated, using an in vitro culture system, the effect of cobalt and/or chromium ions (Co2+ and/or Cr3+ ) on human myoblast proliferation, cellular differentiation, and inflammatory marker expression. Freshly isolated human myoblasts were cultured in media supplemented with graded concentrations of Co2+ and/or Cr3+ . Co2+ induced a concentration-dependent decrease of both myoblast viability and myogenic differentiation while Cr3+ did not. Co2+ or Co2+ /Cr3+ also induced the upregulation of ICAM-1, whereas HLA-DR expression was unaffected. Moreover, allogenic monocytes induced the synergistic increase of Co2+ -induced ICAM-1 expression. We also found that Co2+ stabilized HIF-1α and increased TLR4, tumor necrosis factor-alpha (TNF-α), and interleukin 1ß (IL-1ß) expression in a dose and time-dependent manner in human myoblasts. This study showed that Co2+ , but not Cr3+ , was toxic toward myoblasts and induced, in the surviving cells, expression of inflammatory markers such as ICAM-1, TLR4, TNF-α, and IL-1ß. This suggests that Co2+ , most efficiently in the presence of monocytes, may be a key inducer of ALTR, which may, if severe and long-lasting, eventually result in prosthesis loosening.

Delayed hypersensitivity to palladium dichloride: 15-year retrospective study in a skin allergy unit.

BACKGROUND: Metal allergies are the most frequent causes of allergic contact dermatitis. Although the use of palladium is increasing, it is not included in any baseline series. OBJECTIVE: To assess the prevalence of hypersensitivity to palladium and to describe the clinical and demographic characteristics of patients who are sensitized to palladium dichloride (PdCl2 ). METHODS: A single-centre, retrospective study of 15 years of patch testing with the Spanish baseline series supplemented with PdCl2 2% pet. was performed. We collected clinical and demographic data and data on co-sensitization among the metals studied, and we compared patients who were sensitized to palladium, with or without co-sensitization to nickel, with the rest of the study population. RESULTS: Among the 3678 included patients, 730 (19.9%) were sensitized to nickel sulfate. The prevalence of sensitization to PdCl2 (n = 316, 8.6%) was higher than the prevalence of sensitization to potassium dichromate (n = 240, 6.5%) and similar to the prevalence of sensitization to cobalt chloride (n = 353, 9.6%). Only 26 (8.2%) of the patients sensitized to palladium were not co-sensitized to nickel. The percentage of men and patients aged ≥40 years was higher in this subgroup than in the patients with nickel co-sensitization. CONCLUSIONS: Given the high prevalence of hypersensitivity to PdCl2 , this metal salt should be included in the Spanish baseline series, notwithstanding the frequency of co-sensitization to nickel.

Triterpenoid corosolic acid attenuates HIF-1 stabilization upon cobalt (II) chloride-induced hypoxia in A549 human lung epithelial cancer cells.

Hypoxia-inducible factor-1 is a target for the management of cancer. Here, the anti-proliferation properties of corosolic acid (CA) against A549 human lung epithelial cancer cells in CoCl2-induced hypoxia is reported. CA was isolated from the roots of Salvia syriaca based on a bioassay-guided isolation platform and identified by 1D and 2D NMR experiments. Several cytotoxicies and genotoxicity analyses were performed using MTT, DAPI, cell cycle, DNA ladder, and annexin V/PI detection. Cobalt chloride (CoCl2) was used to stimulate hypoxia. The adaptation of A549 cells to a stimulated hypoxic condition in the presence of CA was evaluated. CA decreased the growth of A549 cells with an IC50 of 12 µg/mL at 48 h. Also, chromatin condensation and DNA fragmentation were detected as signs of apoptosis occurrence. CA induced ~85% apoptosis and even 1% necrosis. The expression of hypoxia-inducible factor-1 α (HIF-1α), HIF-1ß and downstream genes was strongly suppressed in the presence of CA in CoCl2-stimulated hypoxia condition. Results indicated that CA has remarkable cytotoxicity against the cancerous cell in hypoxia condition and may be regarded for preparation of new formulations for possible uses as supplement and medicine in cancer therapy.

Severe Cardiomyopathy Due to Arthroprosthetic Cobaltism: Report of Two Cases with Different Outcomes.

Cobalt-induced cardiomyopathy is a well-known but uncommon disease, and the physician must maintain a high index of suspicion in order to make a timely diagnosis. We report two patients with cobalt-induced cardiomyopathy. Both patients developed progressively worsening symptoms of cobalt toxicity following revision of a fractured ceramic-on-ceramic total hip replacement to a metal-on-polyethylene bearing. In both patients, echocardiography showed LV hypertrophy, biventricular systolic dysfunction, and a large amount of pericardial effusion. Due to decompensated heart failure, both patients were initially considered candidates for heart transplantation. One patient was diagnosed with cobalt-induced cardiomyopathy before transplantation. He received cobalt chelation therapy and revision surgery, which led to complete recovery of heart function. In the other patient, the diagnosis was not made until the time of heart transplantation. The gross examination of the explanted heart revealed typical features of cobalt cardiotoxicity, which was then diagnosed as cobalt-induced cardiomyopathy. These cases emphasise the importance of early diagnosis and prompt treatment of cobalt intoxication.

Cobalt toxicity in humans-A review of the potential sources and systemic health effects.

Cobalt (Co) and its compounds are widely distributed in nature and are part of numerous anthropogenic activities. Although cobalt has a biologically necessary role as metal constituent of vitamin B12, excessive exposure has been shown to induce various adverse health effects. This review provides an extended overview of the possible Co sources and related intake routes, the detection and quantification methods for Co intake and the interpretation thereof, and the reported health effects. The Co sources were allocated to four exposure settings: occupational, environmental, dietary and medical exposure. Oral intake of Co supplements and internal exposure through metal-on-metal (MoM) hip implants deliver the highest systemic Co concentrations. The systemic health effects are characterized by a complex clinical syndrome, mainly including neurological (e.g. hearing and visual impairment), cardiovascular and endocrine deficits. Recently, a biokinetic model has been proposed to characterize the dose-response relationship and effects of chronic exposure. According to the model, health effects are unlikely to occur at blood Co concentrations under 300µg/l (100µg/l respecting a safety factor of 3) in healthy individuals, hematological and endocrine dysfunctions are the primary health endpoints, and chronic exposure to acceptable doses is not expected to pose considerable health hazards. However, toxic reactions at lower doses have been described in several cases of malfunctioning MoM hip implants, which may be explained by certain underlying pathologies that increase the individual susceptibility for Co-induced systemic toxicity. This may be associated with a decrease in Co bound to serum proteins and an increase in free ionic Co2+. As the latter is believed to be the primary toxic form, monitoring of the free fraction of Co2+ might be advisable for future risk assessment. Furthermore, future research should focus on longitudinal studies in the clinical setting of MoM hip implant patients to further elucidate the dose-response discrepancies.

Review of cobalt toxicokinetics following oral dosing: Implications for health risk assessments and metal-on-metal hip implant patients.

Cobalt (Co) can stimulate erythropoietin production in individuals at doses exceeding 25 mg CoCl2/day. Co has also been shown to exert effects on the thyroid gland, heart and nervous system at sufficient doses. The biological activity of Co is dictated by the concentration of free (unbound) ionic Co(2+). Blood concentrations, as well as, urinary excretion rates of Co are reliable biomarkers for systemic Co exposure. A recent series of human volunteer Co-supplement studies simultaneously measured Co blood and urine concentrations, as well as, Co speciation in serum, and a number of biochemical and clinical parameters. It was found in these studies that peak Co whole blood concentration as high as 117 µg/L were not associated with changes in hematological parameters such as increased red blood cell (RBC) count, hemoglobin (Hgb) or hematocrit (Hct) levels, nor with changes in cardiac, neurological or, thyroid function. Using a Co biokinetic model, the estimated Co systemic tissue concentrations (e.g., liver, kidney, and heart) following 90-days of Co-dietary supplementation with ∼1 mg Co/day were found to be similar to estimated tissue concentrations in implant patients after 10 years of exposure at continuous steady state Co blood concentration of ∼10 µg/L. This study is the first to present modeled Co tissue concentrations at various doses following sub-chronic and chronic exposure. The modeled steady state tissue Co concentrations in combination with the data on adverse health effects in humans should help in the characterization of potential hazards associated with increased blood Co concentrations due to exposure to dietary supplements or cobalt-chromium (Co-Cr) containing implants.

Effects and blood concentrations of cobalt after ingestion of 1 mg/d by human volunteers for 90 d.

BACKGROUND: Over-the-counter cobalt supplements are available for sale in the United States, but little is known regarding their clinical effects and biokinetic distribution with long-term use. OBJECTIVE: We assessed blood kinetics, biochemical responses, and clinical effects in 5 adult men and 5 adult women who voluntarily ingested ∼ 1.0 mg Co/d (0.080-0.19 mg Co · kg⁻¹ · d⁻¹) of a commercially available cobalt supplement over a 3-mo period. DESIGN: Volunteers were instructed to take the cobalt dietary supplement in the morning according to the manufacturer's label. Blood samples were collected and analyzed for a number of biochemical variables before, during, and after dosing. Hearing, vision, cardiac, and neurologic functions were also assessed in volunteers before, during, and after dosing. RESULTS: After ∼ 90 d of dosing, mean cobalt blood concentrations were lower in men than in women. Mean cobalt whole blood and serum concentrations in men were 20 µg/L (range: 12-33 µg/L) and 25 µg/L (range: 15-46 µg/L), respectively. In women, mean cobalt whole blood and serum concentrations were 53 µg/L (range: 6-117 µg/L) and 71 µg/L (range: 9-149 µg/L), respectively. Estimated red blood cell (RBC) cobalt concentrations suggested that cobalt was sequestered in RBCs during their 120-d life span, which resulted in a slower whole blood clearance compared with serum. The renal clearance of cobalt increased with the serum concentration and was, on average, lower in women (3.5 ± 1.3 mL/min) than in men (5.5 ± 1.9 mL/min). Sex-specific differences were observed in cobalt absorption and excretion. There were no clinically significant changes in biochemical, hematologic, and clinical variables assessed in this study. CONCLUSION: Peak cobalt whole blood concentrations ranging between 9.4 and 117 µg/L were not associated with clinically significant changes in basic hematologic and clinical variables.

Astragalus saponins downregulate vascular endothelial growth factor under cobalt chloride-stimulated hypoxia in colon cancer cells.

BACKGROUND: Our ongoing research has revealed that total saponins extracted from the medicinal herb Radix Astragali (AST) exhibits significant growth-inhibitory and proapoptotic effects in human cancer cells. In the present study, the potential of AST in controlling angiogenesis was further investigated with elaboration of the underlying molecular mechanism in human colon cancer cell and tumor xenograft. RESULTS: AST decreased the protein level of VEGF and bFGF in HCT 116 colon cancer cells in a time- and dose-dependent manner. Among the Akt/mTOR signal transduction molecules being examined, AST caused PTEN upregulation, reduction in Akt phosphorylation and subsequent activation of mTOR. AST also suppressed the induction of HIF-1α and VEGF under CoCl2-mimicked hypoxia. These effects were intensified by combined treatment of AST with the mTOR inhibitor rapamycin. Despite this, our data also indicate that AST could attenuate cobalt chloride-evoked COX-2 activation, while such effect on COX-2 and its downstream target VEGF was intensified when indomethacin was concurrently treated. The anti-carcinogenic action of AST was further illustrated in HCT 116 xenografted athymic nude mice. AST significantly suppressed tumor growth and reduced serum VEGF level in vivo. In the tumor tissues excised from AST-treated animals, protein level of p-Akt, p-mTOR, VEGF, VEGFR1 and VEGFR2 was down-regulated. Immunohistochemistry has also revealed that AST effectively reduced the level of COX-2 in tumor sections when compared with that in untreated control. CONCLUSION: Taken together, these findings suggest that AST exerts anti-carcinogenic activity in colon cancer cells through modulation of mTOR signaling and downregulation of COX-2, which together reduce VEGF level in tumor cells that could potentially suppress angiogenesis.

The effect of excess cobalt on milk fatty acid profiles and transcriptional regulation of SCD, FASN, DGAT1 and DGAT2 in the mammary gland of lactating dairy cows.

The main objective of this study was to investigate the effect of excess cobalt (Co) on gene expression of stearoyl-CoA desaturase (SCD), fatty acid synthase (FASN), diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2) of lactating dairy cows in relation to milk fatty acid profile. Seven multiparous cows of the Norwegian Red cattle breed (NRF) had their basal diet supplemented with 1.4 g Co as a 24 g/l solution of Co-acetate per os twice daily for 7 days followed by a 9-day depuration period. Udder biopsies were performed prior to the treatment period, after 1 week of treatment and immediately after the depuration period. Excess Co reduced the proportion of all cis-9 monounsaturated fatty acids and increased the proportion of 18:0 in milk. However, gene expression levels of SCD, DGAT1, DGAT2 and FASN were not significantly altered. Our results indicate that the effect of Co on milk fatty acid profile is mediated at the post-transcriptional level by reduced activity of SCD in the mammary gland. Potential mechanisms explaining how Co might reduce stearoyl-CoA desaturation are discussed.

Age-related impairments of mobility associated with cobalt and other heavy metals: data from NHANES 1999-2004.

Exposure to heavy metals promotes oxidative stress and damage to cellular components, and may accelerate age-related disease and disability. Physical mobility is a validated biomarker of age-related disability and is predictive of hospitalization and mortality. Our study examined associations between selected heavy metals and impaired lower limb mobility in a representative older human population. Data for 1615 adults aged >or=60 yr from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 were used to identify associations between urinary concentrations of 10 metals with self-reported and measured significant walking impairments. Models were adjusted for confounding factors, including smoking. In models adjusted for age, gender, and ethnicity, elevated levels of cadmium, cobalt, and uranium were associated with impairment of the ability to walk a quarter mile. In fully adjusted models, cobalt was the only metal that remained associated: the odds ratio (OR) for reporting walking problems with a 1-unit increase in logged cobalt concentration (mug/L) was 1.43 (95% CI 1.12 to 1.84). Cobalt was also the only metal associated with a significant increased measured time to walk a 20-ft course. In analyses of disease categories to explain the mobility finding, cobalt was associated with physician diagnosed arthritis (1-unit increase OR = 1.22 (95% CI 1.00 to 1.49). Low-level cobalt exposure, assessed through urinary concentrations of this essential heavy metal, may be a risk factor for age-related physical impairments. Independent replication is needed to confirm this association.

Characteristics of chelation ability of chosen metal ions by protective ointments containing Na2H2EDTA.

Allergy contact dermatitis is a common occupational disease and the protective ointments are often used by the sensitized subjects. The efficacy of the chelation ability of the barrier creams containing Na2H2EDTA was evaluated. The in vitro test with the diffusion chamber and artificial membrane was performed. The effect of the Na2H2EDTA concentration (3, 5 or 10%), pH of the buffer for Na2H2EDTA dissolving and the vehicle of the ointment on the chelation of Ni2+ and Co2+ were assessed. The ointment with 10% Na2H2EDTA dissolved in the buffer of pH 7.0 or 7.4 buffer was found as optimal for the protection ability. There was no influence of the formula of the ointements on the efficiency of chelation.

Foetal rat lung epithelial (FRLE) cells: partial characterisation and response to pneumotoxins.

Cultured cell lines are routinely used for in vitro toxicity screens, reducing the requirement for animal studies during the development of new pharmaceutical, agrochemical and cosmetic products. The foetal rat lung epithelial (FRLE) cell line was originally derived from alveolar type II cells (ATII) of the lung. The aims of this study were to further characterise FRLE cells and investigate their potential for screening for pneumotoxins. The cells were found to have retained some of the features of their progenitor cells, namely the expression of cytokeratin proteins, specifically cytokeratin 18, and the ability to actively accumulate the non-selective contact herbicide paraquat. However, the cells have lost the ability to synthesise surfactant protein mRNA and no longer contain multiple lamellar bodies. Toxins that damage ATII cells in vivo (cadmium chloride, cobalt chloride and paraquat) were found to induce cytotoxicity in FRLE cells, as did the non-specific pneumotoxin nitrofurantoin, and hydrogen peroxide. However, the cells were less sensitive to the effects of compounds that require metabolic activation (1-nitronaphthalene, coumarin and butylated hydroxytoluene) and the hepatotoxin bromobenzene. Thus, FRLE cells appear to be a good in vitro model for monitoring the potential toxicity to ATII cells and could be used as an initial screen for pneumotoxicity.

Absence of significant genotoxicity in lymphocytes and urine from workers exposed to moderate levels of cobalt-containing dust: a cross-sectional study.

Mortality studies have shown that, in the past, lung cancer occurred after exposure to mixtures of cobalt metal and metallic carbide particles, the main constituents of hard metals, but apparently not when exposure was to cobalt alone. The major objective of this biomonitoring study was to assess genotoxic effects as a measure for carcinogenic risk in workers from cobalt refineries and hard metal plants currently exposed to the threshold limit value/time-weighted average (TLV-TWA) for cobalt-containing dust. The study comprised three groups of workers: 35 workers exposed to cobalt dust from three refineries, 29 workers exposed to hard metal dust from two producing plants, and 35 matched control subjects recruited from the respective plants. The study design integrated complementary methodologies to assess biomarkers of effects that represent both initial DNA damage (8-hydroxydeoxyguanosine [8-OHdG] in urine and comet assay on lymphocytes) and definitive chromosome breakage/loss (micronuclei in lymphocytes). Cobalt and cotinine were determined in urine as a measure for cobalt exposure and recent smoking, respectively. No significant increase of genotoxic effects was detected in workers exposed to cobalt-containing dust as compared to controls. No difference in any genotoxicity biomarker was found between workers exposed to cobalt and hard metal dusts. Multiple regression analysis indicated that workers who smoked and were exposed to hard metal dusts had elevated 8-OHdG and micronuclei values. Because this observation is in line with a previous epidemiological study of an increased risk of dying from lung cancer in workers from the hard metal industry who smoked, it is concluded that this specific occupational group needs closer medical surveillance.

The effects of sucralfate suspension and diphenhydramine syrup plus kaolin-pectin on radiotherapy-induced mucositis.

A prospective, double-blind study compared the effectiveness of sucralfate suspension with diphenhydramine syrup plus kaolin-pectin in reducing severity and pain of radiation-induced oropharyngeal mucositis. Fourteen patients who received at least 4600 cGy to the oral cavity used one of the mouth rinses four times a day, beginning at 1600 cGy. Data were collected on daily perceived pain and helpfulness of mouth rinse, weekly mucositis grade, weight change, and interruption of therapy. Analysis of data revealed no statistically significant differences between the two groups in any parameter. A retrospective review of 15 patients who had received at least 4600 cGy radiation to the oropharynx but had not used a daily mouth-coating rinse, was compared with the study group. Comparison of the two groups suggested that consistent daily oral hygiene and use of a mouth-coating agent will result in less pain and may reduce weight loss and interruption of radiation because of severe mucositis.