The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation.

Etoposide (Eto) is a toxic drug that shows promise in treating prostate cancer (PCa) but confers significant side effects, and has poor solubility and bioavailability. Nanoparticles are quite successful in overcoming such problems. Multifunctional nanoparticles that provide an opportunity to perform combination therapy have attracted great interest in recent years. Superparamagnetic iron oxide nanoparticles (SPIONs) are popular in various biomedical applications, including magnetic resonance imaging, drug delivery, magnetic hyperthermia and recently in photothermal therapy, combining imaging with therapy. Here, for the enhanced killing of PCa cells that are either androgen-dependent or not, the combination of SPION based Eto delivery and mild hyperthermia triggered by laser irradiation is proposed for the first time in the literature. For the encapsulation of Eto, highly stable, small, polyacrylic acid coated SPIONs were conjugated with bovine serum albumin (BSA) (Eto-BSA@PAA@SPION). Eto-BSA@PAA@SPION with 9% drug content produced better chemotherapeutic outcomes than free Eto on both androgen-dependent/castration sensitive LNCaP and androgen-independent/castration-resistant PC3 and DU145 PCa cells by enhancing drug internalization. Single and short irradiation of Eto-BSA@PAA@SPION treated cells at 808 nm improved the drug release and sensitized cells for Eto, hence, increasing the toxicity dramatically in all studied PCa cell lines. Caspase-mediated apoptosis, DNA damage, and ROS generation were detected in the treated cells, increasing with the Eto dose and laser treatment. The IC50 for Eto is reduced to 0.08 µg mL-1, 0.13 µg mL-1 and 2.8 µg mL-1 with laser/Eto-BSA@PAA@SPION for LNCaP, DU145 and PC3 cells, respectively. These are the lowest IC50 values seen in the literature for Eto on these cell lines so far, suggesting that the demonstrated nanoparticles and treatment approaches have great potential to treat various PCa cells at low doses of the drug under mild laser treatment conditions.

Computer-aided prediction and cytotoxicity evaluation of dithiocarbamates of 9,10-anthracenedione as new anticancer agents.

Anticancer activity as an associated action for a series of dithiocarbamates of 9,10-anthracenedione was predicted using the PASS computer program and analysed with PharmaExpert software. The predicted cytotoxic activity of the dithiocarbamate derivatives of 9,10-anthracenedione was evaluated in vitro on cancer cells of the human lung (A549), prostate (PC3), colon (HT29) and human breast (MCF7) using the sulforhodamine B (SRB) cell viability assay. Among these compounds, 9,10-dioxo-9,10-dihydroanthracen-1-yl pyrrolidin-1-carbodithioate and 9,10-dioxo-9,10-dihydroanthracen-2-yl pyrrolidin-1-carbodithioate were identified as the most potent anticancer agents with cytotoxic activity against the MCF-7 human breast cell line with GI50 values of 1.40 µM and 1.52 µM, whereas the GI50 value for the reference anticancer drug mitoxantrone was 3.93 µM. Thus, anticancer activity predicted by PASS with a probability Pa > 30% was confirmed by the experiment. Relatively small Pa values estimated by PASS indicated the novelty of the considered derivatives comparing to the compounds from the PASS training set.

Parmelia sulcata Taylor and Usnea filipendula Stirt induce apoptosis-like cell death and DNA damage in cancer cells.

OBJECTIVES: Successful cancer treatments still require more compounds to be isolated from natural sources. Thus, we have investigated anti-proliferative/apoptotic effects of methanolic extracts of lichen species Parmelia sulcata Taylor and Usnea filipendula Stirt on human lung cancer (A549, PC3), liver cancer (Hep3B) and rat glioma (C6) cells. MATERIALS AND METHODS: Anti-proliferative effects were monitored by MTT and adenosine triphosphate viability assays, while genotoxic activity was studied using the comet assay. Additionally, cell death mode and apoptosis assays (fluorescence staining, caspase-cleaved cytokeratin 18, caspase-3 activity and PARP cleavage) were performed. RESULTS: Extracts produced anti-population growth effects in a dose-dependent manner (1.56-100 µg/ml) by inducing apoptosis-like cell death. This resulted in the lines having the presence of pyknotic cell nuclei. In addition, significant increase in genetic damage in the cell lines was seen, indicating that DNA damage may have been responsible for apoptotic cell death. CONCLUSION: In this study, methanolic extracts of Parmelia sulcata and Usnea filipendula induced apoptosis-like cell death by causing DNA damage, to cancer cells.

Toward a biochemical diagnosis of NASH: insights from pathophysiology for distinguishing simple steatosis from steatohepatitis.

With the continuing epidemics of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) has received increased attention. Great efforts are being undertaken to improve the noninvasive diagnosis of NAFLD, with the ultimate goal of optimizing treatment options and clinical outcomes. Research suggests that blood-borne biochemical markers can be used to distinguish simple steatosis from nonalcoholic steatohepatitis (NASH), thus reducing the need of liver biopsy. Future developments in the field of diagnostic biochemistry within the spectrum of NAFLD can make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different blood-borne markers which have been recently proposed for differentiating simple steatosis from NASH. We will also consider the practical and statistical issues that seem to be limiting the effective integration of biomarkers into clinical development.

Cytokine gene polymorphism and postreperfusion syndrome during orthotopic liver transplantation.

UNLABELLED: The molecular basis underlying the clinical response to acute liver stress remains to be clarified. Postreperfusion syndrome (PRS) occurring after the meeting of grafted liver with the recipient blood is characterized by hemodynamic instability that develops immediately after reperfusion of an orthotopic liver transplantation (OLT). Cytokines have a role during PRS. The aim of this study was to evaluate the role of some cytokine gene polymorphisms on PRS in patients. MATERIALS AND METHODS: Forty-six patients who underwent OLT were divided into two groups: with versus without PRS. Cytokine genotyping using patient blood was determined by the PCR-SSP method. RESULTS: Liver transplant patients as a whole are usually characterized as low producers of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, high producers of transforming growth factor (TGF)-beta1 and IL-6 and intermediate producers of interferon (IFN)-gamma. However no significant relationship was shown between the development of PRS and cytokine gene polymorphisms of TNF-alpha (-308 G/A), TGF-beta1 (C/T codon 10, C/G codon 25), IL-10 (-1082 G/A, -819 T/C, -592 A/C), IL-6 (-174 G/C), or IFN-gamma (+874 A/T). CONCLUSION: It seemed that our limited data did not substantiate a role of certain cytokine gene polymorphisms on PRS occurence during OLT. A larger study population may be required to examine this relationship.

Soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) is decreased in lung cancer patients showing progression: a pilot study.

Tumor growth and metastasis depend on angiogenesis, and the vascular endothelial growth factor (VEGF) is known to be one of the most important angiogenic factors although the knowledge about its receptors is limited. We, therefore, investigated the treatment-related changes both in the level of the soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) in the serum by ELISA and the expression of VEGFR-1 in cancer tissues by immunohistochemistry. The serum levels were studied in 38 lung cancer patients, and 55 control subjects (21 benign disease and 34 healthy subjects) before the chemotherapy. The treatment-related changes in serum sVEGFR-1 were evaluated in 15 patients 24 and 48 hours after treatment. In addition to serum analysis, the tissue expressions were evaluated in 32 patients before treatment. The treatment-related changes in tissue VEGFR-1 expressions were evaluated in only 12 patients 24 hours after treatment. We observed no significant difference in terms of serum sVEGFR-1 levels between malignant and nonmalignant groups (p > 0.05). There were no significant differences in the levels of sVEGFR-1 before and after treatment (p > 0.05). However, there was a significant difference between sVEGFR-1 levels in the groups (regressive, stable, progressive) classified according to the response to therapy (p = 0.043). A significant difference also was present between the expression levels of tissue VEGFR-1 in the same groups (p = 0.037). As a conclusion, we suggest that prechemotherapy sVEGFR-1 can be helpful for prediction of long-term response to therapy, but it should be studied in larger groups to elucidate its benefit in clinics.

Cytokine gene polymorphism and early graft rejection in liver transplant recipients.

Cytokines, which play important roles in allograft rejection, show variable production among individuals. These variations may be related to genetic polymorphisms within the regulatory regions of the cytokine genes. We investigated the association between the role tumor necrosis factor alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interferon gamma (IFN-gamma), interleukin (IL)-10 and IL-6 gene polymorphisms and early graft rejection among liver transplant recipients. Forty-three liver transplant recipients enrolled in this study were divided into 2 groups based on events in the first 2 months posttransplantations, namely, those experiencing at least 1 rejection episode (n = 26) or those without any episode (n = 17). The allele or genotype frequencies of cytokine gene polymorphisms showed no difference between liver recipients with or without nonrejection. In conclusion, there was no significant correlation between early graft rejection and cytokine gene polymorphism of TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma in liver transplant recipients.

4-(N-hydroxyphenyl)retinamide can selectively induce apoptosis in human epidermoid carcinoma cells but not in normal dermal fibroblasts.

The retinoid 4-(N-hydroxyphenyl)retinamide (4HPR, fenretinide) has both growth inhibitory and apoptosis-inducing effects on a number of cancer cell lines in vitro and in vivo and has been entered into a number of oncological trials. However, little is known about its mechanism(s) of action or its effects on normal cells such as fibroblasts. In this study, the effects of fenretinide on both epidermoid carcinoma cells of vulva (cell line A431) and normal human dermal fibroblasts, both as monolayers and also grown in 3D cell culture systems, have been investigated. The 3D cell culture system contained normal human fibroblasts embedded in a type I collagen gel with the carcinoma cells seeded on top of the collagen gel, which mimics the epidermoid carcinoma. Fenretinide significantly inhibited the rate of DNA synthesis of carcinoma cells, while there was little effect on fibroblasts on monolayers, at 10(-6)-10(-5) M, which are clinically attainable doses. Fenretinide at 5 x 10(-6) M induced apoptosis characterised by cell shrinkage, membrane blebbing, nuclear condensation and/or fragmentation, and cell detachment in carcinoma cells, but not fibroblasts from monolayers. Fenretinide also reduced the viability of carcinoma cells in the 3D cell culture system without affecting fibroblasts. These data show that fenretinide may preferentially induce apoptosis in epidermoid carcinoma cells.

Fenretinide and its relation to cancer.

Retinoids, natural or synthetic substances which have vitamin A activity, have a well-known reputation for their antitumour and differention-inducing activity in vitro and in vivo. More than 1500 retinoids have been tested so far but very few of them have been entered into clinical trials because of their side-effects. All-trans-N-(4-hydroxyphenyl)retinamide (4HPR or fenretinide) is a synthetic retinoid that is reported to have fewer side-effects compared to naturally occurring retinoids such as all-trans retinoic acid (ATRA) and 9-cis retinoic acid. In addition, fenretinide has been shown to induce cell death (apoptosis) even in ATRA-resistant cell lines. Although the mechanism by which fenretinide acts is not entirely known it is considered to be a promising drug and seems to induce apoptosis via different pathway(s) from classical retinoids. In this review, we discuss possible mechanisms of fenretinide action and summarize results of clinical trials.

The effect of melatonin on lipid peroxidation during radiotherapy in female rats.

BACKGROUND: Because radiotherapy is one of the causes of primary or secondary ovarian failure, protection of ovarian functions in the patients receiving total body or pelvic radiotherapy is of importance. In this study, we investigated the role of melatonin in the oxidative damage in both whole body and ovaries, which is caused by radiotherapy. MATERIALS AND METHODS: Eighteen female rats were divided into 3 groups, each of which consisted of 6 rats. First group was control group receiving no treatment, second group received total body radiotherapy (RT) by 2 x 360 cGy only and third group received radiotherapy plus melatonin. Malondialdehyde (MDA) levels in both blood and ovarian tissue were detected as the indicator of free radical (FR) damage. Levels of erythrocyte superoxide dismutase (SOD) and glutathion peroxidase (GPX) in blood were measured as the indicators of antioxidant level. RESULTS: Radiotherapy caused a significant increase in the levels of MDA in blood and ovarian tissue (p < 0.001). However, MDA levels decreased in the radiotherapy plus melatonin group (p < 0.05). SOD and GPX levels decreased insignificantly in the radiotherapy only group while they increased in the radiotherapy plus melatonin group significantly (p < 0.01 and p < 0.05, respectively). CONCLUSION: Melatonin, in rats, reduced the level of MDA, which is elevated by radiotherapy and increased the levels of SOD and GPX, which are involved in the antioxidant system.

Effects of smoking on serum lipid and lipoprotein concentrations and lecithin: cholesterol acyltransferase activity.

Cigarette smoking is one of the major risk factors for cardiovascular disease. The mechanism responsible for this association is still unknown. We measured the activity of lecithin: cholesterol acyltransferase (LCAT), a key factor in the esterification of plasma cholesterol and reverse cholesterol transport, and the levels of lipids and apolipoproteins in the serum of 27 cigarette smoking and 31 non-smoking (control) men. We could not find any significant difference among these parameters between the groups. Serum LCAT activity was lower in smokers, but the difference was statistically nonsignificant. We also classified the two groups in respect to their serum lipid levels as hyper- and normolipidemic, we observed that normolipidemic-smokers had lower (p < 0.05) high density lipoprotein-cholesterol (HDL-C) and HDL-ester cholesterol levels compared to the normolipidemic-nonsmokers. While there were no any significant differences between hyperlipidemic-smokers and nonsmokers with respect to any of the parameters. In the end we have got the idea that smoking seems to affect HDL-C and HDL-ester cholesterol levels in the normolipidemic-smokers group, only, Also, LCAT activity tended to be lower in smokers compared to nonsmokers.