Significance of Tissue Expression and Serum Levels of Angiopoietin-like Protein 4 in Breast Cancer Progression: Link to NF-κB /P65 Activity and Pro-Inflammatory Cytokines.

BACKGROUND: The molecular mechanisms linking breast cancer progression and inflammation still remain obscure. The aim of the present study was to investigate the possible association of angiopoeitin like protein 4 (ANGPTL4) and its regulatory factor, hypoxia inducible factor-1 α (HIF-1α), with the inflammatory markers nuclear factor kappa B/p65 (NF-κB /P65) and interleukin-1 beta (IL-1ß) in order to evaluate their role in inflammation associated breast cancer progression. MATERIALS AND METHODS: Angiopoietin-like protein 4 (ANGPTL4) mRNA expressions were evaluated using quantitative real time PCR and its protein expression by immunohistochemistry. DNA binding activity of NF-κB /P65 was evaluated by transcription factor binding immunoassay. Serum levels of ANGPTL4, HIF-1α and IL-1ß were immunoassayed. Tumor clinico-pathological features were investigated. RESULTS: ANGPTL4 mRNA expressions and serum levels were significantly higher in high grade breast carcinoma (1.47±0.31 and 184.98±18.18, respectively) compared to low grade carcinoma (1.21±0.32 and 171.76±7.58, respectively) and controls (0.70±0.02 and 65.34±6.41, respectively), (p<0.05). Also, ANGPTL4 high/moderate protein expression was positively correlated with tumor clinico-pathological features. In addition, serum levels of HIF-1α and IL-1ß as well as NF-κB /P65 DNA binding activity were significantly higher in high grade breast carcinoma (148.54±14.20, 0.79±0.03 and 247.13±44.35 respectively) than their values in low grade carcinoma ( 139.14±5.83, 0.34±0.02 and 184.23±37.75, respectively) and controls (33.95±3.11, 0.11±0.02 and 7.83±0.92, respectively), (p<0.001). CONCLUSION: ANGPTL4 high serum levels and tissue expressions in advanced grade breast cancer, in addition to its positive correlation with tumor clinico-pathological features and HIF-1α could highlight its role as one of the signaling factors involved in breast cancer progression. Moreover, novel correlations were found between ANGPTL4 and the inflammatory markers, IL-1ß and NF-κB/p65, in breast cancer, which may emphasize the utility of these markers as potential tools for understanding interactions for axes of carcinogenesis and inflammation contributed for cancer progression. It is thus hoped that the findings reported here would assist in the development of new breast cancer management strategies that would promote patients' quality of life and ultimately improve clinical outcomes. However, large-scale studies are needed to verify these results.

Membrane permeability related physicochemical properties of a novel gamma-secretase inhibitor.

Pharmaceutical profiling studies were conducted on a novel prototype gamma-secretase inhibitor, to determine the potential of its oral absorption. Such compounds can be of use in the treatment of Alzheimer's disease (AD). The studies included determination of solubility, dissociation constant (pK(a)), octanol/water partition coefficient (log P) and the capacity factor (k'(IAM)) on immobilized artificial membrane (IAM) chromatographic columns. The compound is very slightly solubility in water (120 +/- 50 microg/mL) but the solubility increased considerably in basic medium (270 +/- 60 microg/mL). The compound exhibited pK(a) of (10.36 +/- 0.11); and log P of (3.36 +/- 0.16) determined by shake-flask method and (3.31 +/- 0.01) determined by high performance liquid chromatography (HPLC). The experimentally determined log P values correlated well with the calculated one of 3.44. The observed log k'(IAM) value of (2.79 +/- 0.04) indicates that the compound can reasonably be expected to have high membrane permeability, and therefore, good absorption profile if taken orally. This conclusion is also supported by other parameters determined.

In vitro release studies of flurbiprofen from different topical formulations.

The release profiles of flurbiprofen (F) from different gel and ointment formulations were studied in order to evaluate factors governing the release process. Carbopol 934P (CAB), poloxamer 407 (POL), and eudragit S100 (EUD) gel bases were used, while emulsion (EML) and polyethylene glycol (PEG) ointments were employed. The release studies were conducted using membraneless diffusion cells and lipophilic receptor medium, isopropyl myristate (IPM). The effects of gelling agent concentrations and the initial drug load on drug release were determined. Hydrogels were observed to give higher amounts of drug release than hydrophobic EUD gel and ointments, despite the lower bulk viscosity of these bases. Flurbiprofen release from CAB gels was 3.06-1.56-fold higher than from other formulations. Over a 4-hr period, the amount of F released was 492.8 and 316.0 micrograms/cm2 from 2% CAB and 25% POL gels, while it was 213.05, 168.61, and 160.9 micrograms/cm2 from EML, 40% EUD, and PEG bases, respectively. The diffusivity of F in the gel bases was an inverse function of the polymer concentrations over the range of 1-3% CAB, 20-30% POL, and 35-45% EUD gels. Drug release was increased from the bases as the initial F concentration increased over the range 0.25-1.0%, while the diffusion coefficient observed an inverse relationship. The CAB and POL gels could be the vehicles of choice for the rapid release and onset of F after topical application.