A Data-Mining Approach for the Quantitative Assessment of Physicochemical Properties of Molecular Compounds in the Skin Flux.

This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol-water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.

Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer.

Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has profound effects on numerous key-signaling molecules, and its deregulation contributes to disease, particularly cancer. Although Pin1-mediated prolyl isomerization of protein servers as a regulatory switch in signaling pathways, the significance of proline isomerase activity in chromatin modifying complex remains unclear. Here, we identify Pin1 as a key negative regulator for suppressor of variegation 3-9 homologue 1 (SUV39H1) stability, a major methyltransferase responsible for histone H3 trimethylation on Lys9 (H3K9me3). Pin1 interacts with SUV39H1 in a phosphorylation-dependent manner and promotes ubiquitination-mediated degradation of SUV39H1. Consequently, Pin1 reduces SUV39H1 abundance and suppresses SUV39H1 ability to induce H3K9me3. In contrast, depletion of Pin1 in cancer cells leads to elevated SUV39H1 expression, which subsequently increases H3K9me3, inhibiting tumorigenecity of cancer cells. In a xenograft model with 4T1 metastatic mouse breast carcinoma cells, Pin1 overexpression increases tumor growth, whereas SUV39H1 overexpression abrogates it. In human breast cancer patients, immunohistochemical staining shows that Pin1 levels are negatively correlated with SUV39H1 as well as H3K9me3 levels. Thus, Pin1-mediated reduction of SUV39H1 stability contributes to convey oncogenic signals for aggressiveness of human breast cancer, suggesting that Pin1 may be a promising drug target for anticancer therapy.

SIRT1-mediated FoxO1 deacetylation is essential for multidrug resistance-associated protein 2 expression in tamoxifen-resistant breast cancer cells.

Our previous studies have shown that multidrug resistance protein 2 (MRP2) is overexpressed in tamoxifen-resistant MCF-7 breast cancer cells (TAMR-MCF-7 cells) and forkhead box-containing protein, O subfamily1 (FoxO1), functions as a key regulator of multidrug resistance 1 (MDR1) gene transcription. This study aimed to investigate the role of FoxO1 in regulating MRP2 gene expression in TAMR-MCF-7 cells. The proximal promoter region of the human MRP2 gene contains four putative FoxO binding sites, and MRP2 gene transcription was stimulated by FoxO1 overexpression in MCF-7 cells. Subcellular fractionation and immunoblot analyses revealed that basal MRP2 expression and nuclear levels of FoxO1 were enhanced in TAMR-MCF-7 cells compared to MCF-7 cells and the enhanced MRP2 gene transcription was suppressed by FoxO1 siRNA. Because nuclear localization of FoxO1 is regulated by SIRT1 deacetylase, we were further interested in whether SIRT1 is involved in MRP2 expression. Overexpression of SIRT1 with FoxO1 potentiated the gene transcriptional activity of MRP2, and the basal activity and expression of SIRT1 was increased in TAMR-MCF-7 cells. In addition, SIRT1 inhibition reduced both the nuclear FoxO1 levels and MRP2 expression and enhanced cytotoxic effects of paclitaxel and doxorubicin in TAMR-MCF-7 cells. These results suggest that FoxO1 activation via SIRT1-mediated deacetylation is closely related with up-regulation of MRP2 in TAMR-MCF-7 cells.

Inhibitory effects of a new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, on activator protein-1 activity and neoplastic cell transformation induced by insulin-like growth factor-1.

Diarylureas and diarylamides derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of diarylurea and diarylamide derivatives, we synthesized a new series of diarylureas and diarylamides containing pyrrolo[3,2-c]pyridine scaffold. In this study, we demonstrate that a N-(3-(4-benzamido-1H-pyrrolo[3,2-c]pyridin-1-yl)phenyl)-4-morpholino-3-(trifluoromethyl)benzamide, KIST101029, inhibits neoplastic cell transformation induced by insulin-like growth factor 1 (IGF-1) in mouse epidermal JB6 Cl41 cells. The KIST101029 compound inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK), c-jun N-terminal kinases (JNK), and mechanistic target of rapamycin (mTOR) signaling pathways induced by IGF-1 in JB6 Cl41 cells, resulting in the inhibition of c-fos and c-jun transcriptional activity. In addition, the KIST101029 inhibited the associated activator protein-1 (AP-1) transactivation activity and cell transformation induced by IGF-1 in JB6 Cl41 cells. Consistent with these observations, in vivo chorioallantoic membrane assay also showed that the KIST101029 inhibited IGF-1-induced tumorigenicity of JB6 Cl41 cells. Importantly, KIST101029 suppressed the colony formation of A375 cells in soft agar. Taken together, these results indicate that a KIST101029 might exert chemopreventive effects through the inhibition of phosphorylation of MAPK and mTOR signaling pathway.

Identification of cis-acting elements and signaling components of high affinity IgE receptor that regulate the expression of cyclooxygenase-2.

Allergic and inflammatory responses are functionally linked through a cascade of signaling events that connect the aggregation of the high affinity IgE receptor (FcεRI) on mast cells and the initiation of cyclooxygenase-2 (COX-2) expression. In this study, we identified the cis-acting elements in the cox-2 promoter that control the expression of COX-2 in RBL-2H3 mast cells. We also investigated how the inflammatory reaction is controlled by the allergic reaction by determining the signaling components employed by FcεRI in the transcriptional regulation of cox-2. Among cis-acting components present in the cox-2 promoter, the CREB binding site, as well as the AP-1 and proximal NF-IL6 binding sites to a lesser extent, were required for the transcriptional regulation of the cox-2 promoter. However, NF-κB and Ets-1 binding sites exerted negative effects on the cox-2 promoter activity. Among the signaling components of FcεRI, Fyn, PI 3-kinase, Akt, and p38 MAPK positively mediated the COX-2 expression. Conventional PKCs and atypical PKCs exerted opposite regulatory effects on the cox-2 promoter activity. Blockade of MEK/ERK pathway inhibited the cox-2 promoter activity and the COX-2 expression. These results reveal intricate functional interactions among different cis-acting elements in the transcriptional regulation of cox-2. Fyn-->PI 3-kinase-->Akt pathway directly stimulate. On the other hand, Lyn-->Syk pathway exerts auxiliary or compensatory influences on COX-2 expression via PKC and MEK/ERK.

p-HPEA-EDA, a phenolic compound of virgin olive oil, activates AMP-activated protein kinase to inhibit carcinogenesis.

Phenolic constituents of virgin olive oil are reported to have antitumor activity. However, the underlying molecular mechanisms and specific target proteins of virgin olive oil remain to be elucidated. Here, we report that dialdehydic form of decarboxymethyl ligstroside aglycone (p-HPEA-EDA), a phenolic compound of virgin olive oil, inhibits tumor promoter-induced cell transformation in JB6 Cl41 cells and suppress cyclooxygenase-2 (COX-2) and tumorigenicity by adenosine monophosphate-activated protein kinase (AMPK) activation in HT-29 cells. p-HPEA-EDA inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation of extracellular signal-regulated kinases 1/2 and p90RSK in JB6 Cl41 cells, resulting in the inhibition of cell proliferation, activator protein-1 transactivation and cell transformation promoted by TPA. Moreover, p-HPEA-EDA strongly inhibited the cell viability and COX-2 expression by activation of AMPK activity in HT-29 cells, resulted from depletion of intracellular adenosine triphosphate. p-HPEA-EDA-induced activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase, phosphorylation of p53 (Ser15) and DNA fragmentation in HT-29 cells, leading to apoptosis. Importantly, p-HPEA-EDA suppressed the colony formation of HT-29 cells in soft agar. In contrast, Compound C, an AMPK inhibitor, and Z-DEVD-FMK, a caspase-3 inhibitor, blocked the p-HPEA-EDA-inhibited colony formation in HT-29 cells. In vivo chorioallantoic membrane assay also showed that p-HPEA-EDA-inhibited tumorigenicity of HT-29 cells. These findings revealed that targeted activation of AMPK and inhibition of COX-2 expression by p-HPEA-EDA contribute to the chemopreventive and chemotherapeutic potential of virgin olive oil against colon cancer cells.

5'-Nitro-indirubinoxime inhibits epidermal growth factor- and phorbol ester-induced AP-1 activity and cell transformation through inhibition of phosphorylation of Pin1.

5'-Nitro-indirubinoxime (5'-NIO), a derivative of indirubin, exhibits anti-cancer activity in a variety of human cancer cells. However, the underlying molecular mechanisms and molecular target(s) of the chemopreventive activities of 5'-NIO remain unknown. Here, we report that 5'-NIO inhibited the epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation of JB6 Cl41 mouse skin epidermal cells without any cytotoxic effects. Western blot analysis revealed that 5'-NIO inhibited activities of Raf-1 (S338), MEK1/2, ERK1/2, JNK, and c-Jun induced by EGF or TPA, respectively, whereas it did not affect autophosphorylation of epidermal growth factor receptor (EGFR) induced by EGF or TPA. In addition, 5'-NIO exerted strong inhibitory effects on the EGF- or TPA-induced c-fos or c-jun transcriptional activity, and thereby inhibited the associated activator protein-1 (AP-1) transactivation activity induced by EGF or TPA. Importantly, 5'-NIO inhibited Pin1 phosphorylation at serine 16 induced by EGF or TPA, respectively, resulted in the inhibition of interaction between Pin1 and Raf-1. Immunoprecipitation/immunoblot analysis revealed that 5'-NIO bound with Pin1. Together, these findings suggest that 5'-NIO might act as an anticarcinogene in EGF- or TPA-induced carcinogenesis through the inhibition of interaction between Pin1 and Raf-1. © 2011 Wiley Periodicals, Inc.

Doxorubicin-loaded solid lipid nanoparticles to overcome multidrug resistance in cancer therapy.

In the present study we developed doxorubicin-loaded solid lipid nanoparticles (SLN-Dox) using biocompatible compounds, assessed the in vitro hemolytic effect, and examined their in vivo effects on drug retention and apoptosis intensity in P-glycoprotein-overexpressing MCF-7/ADR cells, a representative Dox-resistant breast cancer cell line. Our SLNs did not show hemolytic activity in human erythrocytes. In comparison with Dox, SLN-Dox efficiently enhanced apoptotic cell death through the higher accumulation of Dox in MCF-7/ADR cells. Therefore, SLN-Dox have potential to serve as a useful therapeutic approach to overcome the chemoresistance of adriamycin-resistant breast cancer. FROM THE CLINICAL EDITOR: Doxorubicin loaded solid lipid nanoparticles (SLN-Dox) were studied in a cell line representative of doxorubicin resistant breast cancer. The nanoparticles did not show hemolytic activity; furthermore, they efficiently enhanced apoptotic cell death through higher accumulation of doxorubicin in cancer cells. This approach may be viable in overcoming the chemoresistance of adriamycin resistant breast cancer.

A practical guide to the development of microneedle systems - In clinical trials or on the market.

Microneedle systems are a rapidly growing and promising technology for delivery of drugs, such as vaccines, small molecules, or biologics and for aesthetic skin treatment in local clinics; however, they remain relatively new from a regulatory perspective. There are strong demands for established procedures, test requirements for approval, and recent trends that industries/researchers related to microneedle systems can refer to. Some microneedle systems are commercially available, many are currently undergoing clinical trials, and some are pending approval for commercialization. This review focuses on microneedle systems that are either on the market or in clinical trials, their applicability and characteristics, and the critical evaluation and test methods necessary for their development and approval.

The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation.

Phosphorylation of proteins on serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase Pin1 and is a central signaling mechanism in cell proliferation and transformation. Although Pin1 is frequently overexpressed in hepatocellular carcinoma (HCC), the molecular mechanism of Pin1 in HCC has not been completely elucidated. Here, we show that Pin1 interacts with p70S6K in vitro and ex vivo. Overexpression of Pin1 resulted in enhanced p70S6K phosphorylation induced by insulin in SK-HEP-1 cells. In contrast, Pin1(-/-) mouse embryonic fibroblasts (MEFs) exhibited significantly decreased insulin-induced p70S6K phosphorylation compared with Pin1(+/+) MEFs. Furthermore, Pin1 enhanced the insulin-induced extracellular signal-regulated protein kinase (ERK)1/2 phosphorylation through its interaction with p70S6K, whereas the inhibition of p70S6K activity by rapamycin suppressed insulin-induced ERK1/2 phosphorylation in SK-HEP-1 cells. Hence, Pin1 affected activator protein-1 activity through p70S6K-ERK1/2 signaling in SK-HEP-1 cells. Most importantly, Pin1-overexpressing JB6 Cl41 cells enhanced neoplastic cell transformation promoted by insulin much more than green fluorescent protein-overexpressing JB6 Cl41 control cells. These results imply that Pin1 amplifies insulin signaling in hepatocarcinoma cells through its interaction with p70S6K, suggesting that Pin1 plays an important role in insulin-induced tumorigenesis and is a potential therapeutic target in hepatocarcinoma.

Involvement of Pin1 induction in epithelial-mesenchymal transition of tamoxifen-resistant breast cancer cells.

Acquisition of resistance to tamoxifen is a critical therapeutic problem in breast cancer patients. Epithelial-mesenchymal transition (EMT), where cells undergo a developmental switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype, is associated with invasion and motility of cancer cells. Here, we found that tamoxifen-resistant (TAMR)-MCF-7 cells had undergone EMT, as evidenced by mesenchymal-like cell shape, downregulation of basal E-cadherin expression, and overexpression of N-cadherin and vimentin, as well as increased Snail transcriptional activity and protein expression. Given the roles of glycogen synthase kinase (GSK)-3beta and nuclear factor (NF)-kappaB in Snail-mediated E-cadherin deregulation during EMT, we examined the role of these signaling pathways in the EMT of TAMR-MCF-7 cells. Both Ser9-phosphorylated GSK-3beta (inactive form) and NF-kappaB reporter activity were increased in TAMR-MCF-7 cells, as was activation of the phosphatase and tensin homolog depleted on chromosome ten (PTEN)-phosphoinositide 3 (PI3)-kinase-Akt pathway. Pin1, a peptidyl-prolyl isomerase, was overexpressed in TAMR-MCF-7 cells, and Snail transcription and the expression of EMT markers could be decreased by Pin1 siRNA treatment. These results imply that Pin1 overexpression in TAMR-MCF-7 cells is involved in the EMT process via PTEN-PI3-kinase-Akt-GSK-3beta and/or GSK-3beta-NF-kappaB-dependent Snail activation, and suggest the potential involvement of Pin1 in EMT during breast cancer development.

Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression.

Coenzyme Q10 (CoQ10), an endogenous antioxidant, is important in oxidative phosphorylation in mitochondria. It has anti-diabetic and anti-cardiovascular disease effects, but its ability to protect against liver fibrosis has not been studied. Here, we assessed the ability of solubilized CoQ10 to improve dimethylnitrosamine (DMN)-induced liver fibrogenesis in mice. DMN treatments for 3 weeks produced a marked liver fibrosis as assessed by histopathological examination and tissue 4-hydroxyproline content. Solubilized CoQ10 (10 and 30 mg/kg) significantly inhibited both the increases in fibrosis score and 4-hydroxyproline content induced by DMN. Reverse transcription-polymerase chain reaction and Western blot analyses revealed that solubilized CoQ10 inhibited increases in the transforming growth factor-beta1 (TGF-beta1) mRNA and alpha-smooth muscle actin (alpha-SMA) protein by DMN. Interestingly, hepatic glutamate-cysteine ligase (GCL) and glutathione S-transferase A2 (GSTA2) were up-regulated in mice treated with CoQ10. Solubilized CoQ10 also up-regulated antioxidant enzymes such as catalytic subunits of GCL and GSTA2 via activating NF-E2 related factor2 (Nrf2)/antioxidant response element (ARE) in H4IIE hepatoma cells. Moreover, CoQ10's inhibition of alpha-SMA and TGF-beta1 expressions disappeared in Nrf2-null MEF cells. In contrast, Nrf2 overexpression significantly decreased the basal expression levels of alpha-SMA and TGF-beta1 in Nrf2-null MEF cells. These results demonstrated that solubilized CoQ10 inhibited DMN-induced liver fibrosis through suppression of TGF-beta1 expression via Nrf2/ARE activation.

Enhanced expression of aromatase in p53-inactivated mammary epithelial cells.

Both the functional loss of p53 and the overexpression of aromatase are important for the progression of breast cancer in postmenopausal women. Here, we found that aromatase expression was up-regulated in primary cultures of mammary epithelial cells (p53(Delta)(5,6) MEC) isolated from mice with a defect in exons 5 and 6 of the p53 gene. Aromatase basal activity and expression levels were significantly increased in p53(Delta)(5,6) MEC when compared with wild-type MEC. Reporter gene activity in p53(Delta)(5,6) MEC transfected with the aromatase promoter or the cAMP-responsive element (CRE) minimal promoter was higher than wild-type MEC. p53 inactivation increased both Ser133-phosphorylated CRE-binding protein (CREB) and the nuclear accumulation of CREB. Inhibition of extracellular signal-regulated kinase (ERK) or Src tyrosine kinase blocked aromatase gene transactivation and CREB activation in the p53(Delta)(5,6) MEC. These results support the hypothesis that a genetic defect in the function of p53 enhances the expression of aromatase via ERK or Src activation in MEC, which suggests that aromatase expression is closely related to the p53 status in MEC.

Fucoidan from Laminaria cichorioides inhibits AP-1 transactivation and cell transformation in the mouse epidermal JB6 cells.

Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, has anticoagulant and antithrombotic activities. Unlike heparine, fucoidan is known to exhibit anticarcinogenic activities. However, the underlying molecular mechanisms of the chemopreventive activities of fucoidan are not understood. Here we report that fucoidan from Laminaria cichorioides inhibited the epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation, but had less cytotoxic effects on JB6 mouse epidermal cells. The EGF-induced phosphorylation of extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinases, and c-Jun was inhibited by fucoidan, resulting from the inhibition of phosphorylation of epidermal growth factor receptor (EGFR). Fucoidan dose-dependently attenuated the c-fos or c-jun transcriptional activity, and thereby inhibited the associated activator protein-1 (AP-1) transactivation activity. In vitro binding assay revealed that fucoidan directly interacted with EGF, suggested that antitumor promoting effect of fucoidan might be due to preventing the binding of EGF to its cell surface receptor (EGFR). These findings are the first to reveal a molecular basis for the anticarcinogenic action of fucoidan and may partially account for the reported chemopreventive effects of brown seaweeds.

Analysis of meloxicam by high-performance liquid chromatography with cloud-point extraction.

A simple cloud-point extraction method for the determination of meloxicam in human serum was developed. Meloxicam was extracted from serum sample after adding 1 mL of 3% (v/v) Triton X-114 aqueous solution in the presence of 1M HCl and 60 mg NaCl. The meloxicam, present in the surfactant-rich phase, was enriched again with acetonitrile. Tenoxicam was used as the external standard. The separation was achieved on a C18 analytical column with a mobile phase consisting of aqueous acetic acid (1%, v/v) and acetonitrile (54:46, v/v). UV detection was performed at 360 nm. The response was linear over the range 45-2000 ng mL(-1) in human serum, and intra- and interday precisions of less than 15.0% were obtained. The relative error was within +/-3.0%. The recoveries of meloxicam were larger than 92.0%. The method was compared with liquid-liquid extraction. The results showed that the new method has a considerable LOQ and higher recoveries but poorer precision than liquid-liquid extraction, which exhibited poor recoveries of less than 86.0%, precisions of less than 5.0% and relative errors of less than 7.0%. The method was used for the determination of meloxicam in healthy human volunteers.

Preparation of an extended-release matrix tablet using chitosan/Carbopol interpolymer complex.

A chitosan and Carbopol interpolymer complex (IPC) was formed using a precipitation method in an acidic solution. The chitosan and Carbopol IPC was characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and turbidity measurements. FT-IR demonstrated that the IPC formed a complex through an electrostatic interaction between the protonated amine (NH(3)(+)) group of chitosan and the carboxylate (COO(-)) group of Carbopol. DSC indicated the IPC to have different thermal characteristics from chitosan or Carbopol. The turbidity measurement revealed the complexation ratio of IPC between chitosan/Carbopol to be 1/4. A theophylline tablet was prepared using the IPC as a matrix material. The drug release profile from this tablet was similar to that from the HPMC tablet and showed a pH-independent release profile. The mechanisms for drug release from the IPC tablet were diffusional release at pH 6.8 and relaxational release at pH 1.2.

Preparation of Carbopol/chitosan interpolymer complex as a controlled release tablet matrix; effect of complex formation medium on drug release characteristics.

Chitosan/Carbopol971NF (poly acrylic acid) interpolymer complexes were prepared in pH 3.0, 4.0, and 5.0 medium to control the ratio of chitosan and Carbopol971NF in the interpolymer complex. FT-IR analysis confirmed that the mechanism of complexation involved an electrostatic interaction between the NH3+ of chitosan and COO(-) of Carbopol971NF. An increase in the pH of the preparation medium was accompanied by an increase in the ratio of chitosan in the chitosan/Carbopol971NF complex. The maximum yield of interpolymer complexes prepared at pH 3, 4, and 5 (IPC3, IPC4, IPC 5) were obtained at ratios of 1/10, 1/5, and 1/4 (chitosan/Carbopol971NF), respectively. At pH 1.2, the overall drug release from IPC tablets did not show significant differences. However, at pH 6.8, the rate of drug release from the IPC5 tablet was higher than that from the IPC4 tablet. The release rate from the IPC3 tablet was observed to increase with time. The release mechanism was increasingly dominated by the relaxational contribution in the order of IPC3, IPC5, and IPC4 at pH 6.8. The diffusional contribution was dominated only in the early stage of drug release and the relaxational contribution gradually increased with time.

Effect of poloxamer on the dissolution of felodipine and preparation of controlled release matrix tablets containing felodipine.

The effects of poloxamer and HPMC on the dissolution rate of felodipine were investigated and a felodipine controlled release tablet was developed by increasing the water solubility of felodipine and using swelling polymer to control release rate. Milling of felodipine slightly increased the dissolution rate of felodipine when compared with physical mixture. XRD results indicated that felodipine remained in the crystalline form even after co-milling with poloxamer. Improved dissolution rates after co-milling with HPMC and poloxamer were due to both solubilization effect of polymer and milling. The effect of poloxamer on dissolution rate was more significant than that of HPMC. Based on increased solubility of felodipine in the presence of poloxamer, it was concluded that the improved dissolution rate of felodipine was mainly due to a high local concentration of poloxamer around felodipine. Controlled release felodipine tablets were prepared using poloxamer as a solubilizing agent and Carbopol as a controlled release matrix.

Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells.

Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. The transition from chemotherapy-responsive breast cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multidrug resistance-associated proteins (MRPs). In this study, it was found that TAM-resistant MCF-7 (TAMR-MCF-7) cells expressed higher levels of MRP2 than control MCF-7 cells. Molecular analyses using MRP2 gene promoters supported the involvement of the pregnane X receptor (PXR) in MRP2 overexpression in TAMR-MCF-7 cells. Although CCAAT/enhancer-binding protein beta was overexpressed continuously in TAMR-MCF-7 cells, this might not be responsible for the transcriptional activation of the MRP2 gene. In addition, the basal activities of phosphatidylinositol 3-kinase (PI3-kinase) were higher in the TAMR-MCF-7 cells than in the control cells. The inhibition of PI3-kinase significantly reduced both the PXR activity and MRP2 expression in TAMR-MCF-7 cells. Overall, MRP2 induction plays a role in the additional acquisition of chemotherapy resistance in TAM-resistant breast cancer.

Improved absorption of meloxicam via salt formation with ethanolamines.

The present study aimed to investigate the effect of ethanolamine salt formation on the dissolution as well as in vivo pharmacokinetics of meloxicam. Three meloxicam-ethanolamine salts were prepared and their in vitro dissolution profiles were examined at pH 1.2 and 6.8. The pharmacokinetic profiles of meloxicam following an oral administration of meloxicam or its ethanolamine salts were also evaluated in rats. The dissolution rates of meloxicam and its ethanolamine salts were similarly slow at pH 1.2, however, at pH 6.8, ethanolamine salt formation significantly enhanced the dissolution rate of meloxicam. Meloxicam diethanolamine salt exhibited the highest dissolution rate at pH 6.8. The faster dissolution of meloxicam via ethanolamine salt formation at pH 6.8 appeared to be correlated well with more rapid absorption of meloxicam in rats. Tmax of meloxicam was significantly (p<0.05) shortened following an oral administration of ethanolamine salts. Furthermore, ethanolamine salts exhibited a trend toward the increase in AUC0-4 (initial exposure), while the overall exposure (AUC0-24) was similar between meloxicam and its salts. In conclusion, the ethanolamine salts of meloxicam, particularly diethanolamine salt of meloxicam, facilitated the rapid absorption of meloxicam while maintaining the prolonged exposure and may be used for the earlier onset of action for meloxicam.