ABSTRACT
The bioavailability of sulindac (SDC), a nonsteroidal anti-inflammatory drug, is low due to poor aqueous solubility and poor dissolution rate. For this reason it is necessary to enhance the solubility and enhance dissolution of the drug by dispersing SDC in polyethylene glycols 6000 (PEG 6000) and polyvinyl pyrrolidone 40000 (PVP 40000) matrices using the coevaporation technique. Studying the influence of SDC to polymer ratio on drug content, percent yield, particle size, and in vitro release was performed. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to characterize any change in crystal habit of SDC in the prepared formulae. The anti-inflammatory effect of SDC was studied using the hind paw edema model. It was found that incorporation of SDC in PEG 6000 and PVP 40000 matrices resulted in improving the dissolution rate, which was found to depend on the polymer and its weight ratio of the drug. It is clearly obvious that the dissolution rate was remarkably improved in drug PVP 40000 molecular dispersions when compared to drug PEG 6000 systems. Solid dispersion of SDC in PEG and PVP improved the anti-inflammatory effect of SDC and it was found that formula SDV5 exhibited a more pronounced inhibition of swelling than other formulae.
Subject(s)
Drug Carriers/chemistry , Inflammation/drug therapy , Povidone/chemistry , Sulindac/administration & dosage , Sulindac/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Diffusion , Drug Compounding/methods , Drug Evaluation, Preclinical/methods , Inflammation/diagnosis , Inflammation/immunology , Male , Polyethylene Glycols/chemistry , Rats , Rats, Wistar , Solubility , Treatment OutcomeABSTRACT
Cancer stem cells (CSCs) are shown to be responsible for initiation and progression of tumors in a variety of cancers. We previously showed that anthocyanin-containing baked purple-fleshed potato (PP) extracts (PA) suppressed early and advanced human colon cancer cell proliferation and induced apoptosis, but their effect on colon CSCs is not known. Considering the evidence of bioactive compounds, such as anthocyanins, against cancers, there is a critical need to study anticancer activity of PP, a global food crop, against colon CSCs. Thus, isolated colon CSCs (positive for CD44, CD133 and ALDH1b1 markers) with functioning p53 and shRNA-attenuated p53 were treated with PA at 5.0 µg/ml. Effects of baked PP (20% wt/wt) against colon CSCs were also tested in vivo in mice with azoxymethane-induced colon tumorigenesis. Effects of PA/PP were compared to positive control sulindac. In vitro, PA suppressed proliferation and elevated apoptosis in a p53-independent manner in colon CSCs. PA, but not sulindac, suppressed levels of Wnt pathway effector ß-catenin (a critical regulator of CSC proliferation) and its downstream proteins (c-Myc and cyclin D1) and elevated Bax and cytochrome c, proteins-mediating mitochondrial apoptosis. In vivo, PP reduced the number of crypts containing cells with nuclear ß-catenin (an indicator of colon CSCs) via induction of apoptosis and suppressed tumor incidence similar to that of sulindac. Combined, our data suggest that PP may contribute to reduced colon CSCs number and tumor incidence in vivo via suppression of Wnt/ß-catenin signaling and elevation of mitochondria-mediated apoptosis.
Subject(s)
Anthocyanins/chemistry , Colonic Neoplasms/metabolism , Neoplastic Stem Cells/metabolism , Solanum tuberosum/chemistry , Animals , Antineoplastic Agents/chemistry , Apoptosis , Azoxymethane/chemistry , Carcinogenesis , Cell Line, Tumor , Cell Proliferation , Cell Survival , Cell Transformation, Neoplastic/metabolism , Colonic Neoplasms/diet therapy , Colonic Neoplasms/prevention & control , Cytochromes c/metabolism , Food , Humans , In Situ Nick-End Labeling , Lentivirus , Male , Mice , Mitochondria/metabolism , Neoplastic Stem Cells/cytology , RNA, Small Interfering/metabolism , Sulindac/chemistry , Tumor Suppressor Protein p53/metabolism , Wnt Proteins/metabolism , bcl-2-Associated X Protein/metabolism , beta Catenin/metabolismABSTRACT
A light scattering-based amyloid fibril formation assay was employed to evaluate potential inhibitors of transthyretin (TTR) amyloid fibril formation in vitro. Twenty nine aromatic small molecules, some with homology to flufenamic acid (a known non-steroidal anti-inflammatory drug) were tested to identify important structural features for inhibitor efficacy. The results of these experiments and earlier data suggest that likely inhibitors will have aromatic-based structures with at least two aromatic rings. The ring or fused ring system occupying the outermost TTR binding pocket needs to be substituted with an acidic functional group (e.g. a carboxylic acid) to interact with complimentary charges in the TTR binding site. The promising TTR amyloid fibril inhibitors ranked in order of efficacy are: 2 > 4 approximately 7 > 3 > 9 > 6 > 21.