[Show abstract][Hide abstract] ABSTRACT: In breast cancer (BrCa), overexpression of the nuclear co-activator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating BrCa cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating CSF1 expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and BrCa cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes BrCa metastasis, offering a novel therapeutic target for impeding this process.
[Show abstract][Hide abstract] ABSTRACT: The design of smart targeted drug delivery systems that deliver drugs to specific cancer cells will give rise to cancer treatments with better efficacy and lower toxicity levels. We report the development and characterizations of maleimide-functionalized biopolymer (Mal-PGA-Asp) as an effective targeted drug delivery carrier synthesized from an amidation reaction between aspartylated PGA (PGA-Asp) and N-(maleimidohexanoyl)-ethylenediamine (NME). The epidermal growth factor receptor (EGFR) targeting peptide (TP13) was conjugated to Mal-PGA-Asp to obtain the targeting carrier (TP13-Mal-PGA-Asp). Cisplatin was finally loaded by complexation to form a biocompatible and tumor targeted therapeutic drug (TP13-Mal-PGA-Asp3-Pt). The resultant biopolymer with an average size 87 ± 28 nm showed a sustainable release profile with a half-maximal release time (t(1/2)) of approximately 15 h in physiological saline. Fluorescence imaging and flow cytometry analysis revealed that TP13 significantly enhanced the cellular uptake of TP13-Mal-PGA-Asp3-Pt in the human hepatoma cell line SMMC-7721. The IC(50) value demonstrated the superior anticancer activity of TP13-Mal-PGA-Asp3-Pt over PGA-Asp-Pt. Therefore, the newly developed drug carrier (TP13-Mal-PGA-Asp) obtained in this study may provide an efficient and targeted delivery of anticancer drugs, presenting a promising targeted chemotherapy in EGFR-positive cancers.
No preview · Article · Oct 2012 · Journal of Biomedical Materials Research Part A
[Show abstract][Hide abstract] ABSTRACT: Metastatic breast cancer remains a lethal disease with poorly understood molecular mechanisms. Steroid receptor coactivator-1 (SRC-1 or NCOA1) is overexpressed in a subset of breast cancers with poor prognosis. It potentiates gene expression by serving as a coactivator for nuclear receptors and other transcription factors. We previously reported that SRC-1 promotes breast cancer metastasis without affecting primary mammary tumor formation. Herein, we found that SRC-1 deficiency in mouse and human breast cancer cells substantially reduced cell adhesion and migration capabilities on fibronectin and significantly extended the time of focal adhesion disassembly and reassembly. In agreement with this phenotype, SRC-1 expression positively correlated with integrin α(5) (ITGA5) expression in estrogen receptor-negative breast tumors whereas SRC-1 deficiency decreased ITGA5 expression. Furthermore, ITGA5 reduction in SRC-1-deficient/insufficient breast cancer cells or knockdown of ITGA5 in SRC-1-expressing breast cancer cells was associated with a disturbed integrin-mediated signaling. Critical downstream changes included reduced phosphorylation and/or dampened activation of focal adhesion kinase, paxillin, Rac1, and Erk1/2 during cell adhesion. Finally, we found that SRC-1 enhanced ITGA5 promoter activity through an AP-1 (activator protein)-binding site proximal to the transcriptional initiation site; both SRC-1 and c-Jun were recruited to this promoter region in breast cancer cells. These results show that SRC-1 can promote breast cancer metastasis by directly enhancing ITGA5 expression and thus promoting ITGA5-mediated cell adhesion and migration. Therefore, targeting ITGA5 in SRC-1-positive breast cancers may result in inhibition of SRC-1-promoted breast cancer metastasis.
[Show abstract][Hide abstract] ABSTRACT: We have recently synthesized a new platinum derivative, poly (γ, L-glutamic acid)-cisplatin conjugate (γ-PGA-CDDP), and shown that it displayed remarkable antitumor activity against breast tumor in a mouse model. The purpose of this study is to systematically compare this new drug with three platinum derivatives currently used in the clinic: cisplatin, carboplatin and oxaliplatin. Here, we show that γ-PGA-CDDP displays impressive antitumor activity over the current clinically used platinum drugs. More interestingly and more importantly, γ-PGA-CDDP conjugate significantly reduces cytotoxicity, mitigates oxidative stress and improves antioxidative capability in vivo. Animals treated with γ-PGA-CDDP display the same profile of body weight as the control animals, while the tumors in γ-PGA-CDDP-treated animals are significantly suppressed compared with those treated with carboplatin and oxaliplatin. Our data suggest that γ-PGA could be used as an effective carrier for drug delivery and that γ-PGA-CDDP conjugate may have potential therapeutic applications in human cancers that are sensitive to treatment with CDDP-based chemotherapy such as ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: We synthesized a new non-toxic biopolymer (GAP460) containing γ,L-glutamic acid and aspartate (Asp). Conjugates of GAP460 and cisplatin exhibited a drug-carrying capacity of nearly 40%, 3-times higher than γ-PGA and dramatically decreasing the amount of biopolymer required for high-dose delivery. Treatment with GAP460-cisplatin conjugate (PACC) not only effectively inhibited tumor growth in nude mice, but also resulted in extended survival and lower nephrotoxicity, suggesting that GAP460 could be used as an effective carrier for drug delivery and that PACC may have potential therapeutic applications in the clinical treatment of cancer.
No preview · Article · Oct 2010 · Journal of Biomaterials Science Polymer Edition
[Show abstract][Hide abstract] ABSTRACT: Glucagon-like peptide-1 (GLP-1) is a promising new therapeutic agent for the treatment of type 2 diabetes. However, GLP-1 has a short half-life (t(1/)(2)<2min) due to rapid degradation by dipeptidyl peptidase IV in vivo. To circumvent this problem, a recombinant mGLP-1 with a cysteine at the C-terminus of GLP-1 was expressed in Escherichia coli and purified by affinity and reverse-phase chromatography. This addition of a cysteine facilitates mGLP-1 binding to serum albumin both in vitro and in vivo, thus protecting mGLP-1 from protease degradation. Similar to GLP-1, mGLP-1 stimulated cAMP production in PC12 cells and exhibited insulinotropic activity in MIN6 cells under in vitro culture conditions. Importantly, in glucose tolerance tests mice treated with mGLP-1 exhibited much lower glucose levels and much higher insulin levels versus that in mice treated with unmodified GLP-1. Furthermore, the effects of mGLP-1 on reduction of blood glucose levels lasted for 6-7h, while the effects of unmodified GLP-1 only lasted for 0.5-1h after injection. These results demonstrate that mGLP-1 is biologically active and its pharmaceutical efficacy is largely enhanced by the cysteine-mediated covalent conjugation with albumin in the serum after injection. Therefore, the mGLP-1 with a cysteine may be a better potential therapeutic drug than the unmodified GLP-1 for treating type 2 diabetes.
No preview · Article · Sep 2010 · Regulatory Peptides
[Show abstract][Hide abstract] ABSTRACT: Poly-gamma-glutamic acid (gamma-PGA) prepared by fermentation of microbe was used as drug carrier for vanadium sulfate to obtain vanadyl-poly-gamma-glutamic acid (VO-gamma-PGA) complex. The FI-IR spectrum of the complex demonstrated that the expected VO-gamma-PGA complex is formed by the coordination of VO(2+) through the side chain carboxylic groups of the gamma-PGA. Studies of the complex in treating type I diabetes were carried out on alloxan induced diabetes rats. The results of treating the rats in 2 weeks and then stopping administration for 10 days showed that VO-gamma-PGA can effectively lower blood glucose levels of diabetic rats during administration. But after ceasing treatment there were no differences between groups in blood glucose level and water intake. The results of oral glucose tolerance and some serum parameters also demonstrated that VO-gamma-PGA was more effective than vanadium sulfate in treating diabetic rats.
No preview · Article · Jul 2010 · Journal of Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: An electrochemical impedance immunosensor for the detection of Escherichia coli was developed by immobilizing anti-E. coli antibodies at an Au electrode. The immobilization of antibodies at the Au electrode was carried out through a stable acyl amino ester intermediate generated by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydrosuccinimide (NHS), which could condense antibodies reproducibly and densely on the self-assembled monolayer (SAM). The surface characteristics of the immunosensor before and after the binding reaction of antibodies with E. coli were characterized by atomic force microscopy (AFM). The immobilization of antibodies and the binding of E. coli cells to the electrode could increase the electro-transfer resistance, which was directly detected by electrochemical impedance spectroscopy (EIS) in the presence of Fe(CN)63−/Fe(CN)64− as a redox probe. A linear relationship between the electron-transfer resistance and the logarithmic value of E. coli concentration was found in the range of E. coli cells from 3.0×103 to 3.0×107cfumL−1 with the detection limit of 1.0×103cfumL−1. With preconcentration and pre-enrichment steps, it was possible to detect E. coli concentration as low as 50cfu/mL in river water samples.
No preview · Article · May 2008 · Electrochimica Acta
[Show abstract][Hide abstract] ABSTRACT: A platinum nanoparticles chemically modified electrode (PtNP/GCE) was fabricated by electro-deposition and used to detection of Escherichia coli (E. coli). The detection principle was based on determination of p-aminophenol that was produced by an enzymatic reaction in E. coli solution. The sensitivity of the detection was improved by the platinum nanoparticle modified electrode and optimization of the detection system. The current responses were proportional to the density of E. coli ranging from 50 to 1.0×105 cfu/mL, with detection limit of 20 cfu/mL, and the detection time was less than 4 h. Compared with conventional methods, the electrochemical technology described here could be suitable for rapid detection of E. coli in the fields of food industry, environmental monitoring and clinic biomedicine.
No preview · Article · Feb 2008 · Chinese Journal of Chemistry
[Show abstract][Hide abstract] ABSTRACT: An amperometric method for the rapid detection of Escherichia coli (E. coli) by flow injection analysis (FIA) using an IrO2–Pd chemically modified electrode (CME) was developed in this paper. The method is based on a good marker β-d-galactosidase which was found in E. coli strains. β-d-galactosidase was produced by the induction of isopropyl β-d-thiogalactopyranoside (IPTG) and released from E. coli cells through the permeabilization of both polymyxin B nonapeptide and lysozyme to E. coli cells wall. The released β-d-galactosidase could catalyze the hydrolysis of the substrate p-aminophenyl β-d-galactopyranoside (PAPG) in the culture medium to produce 4-aminophenol which was proportional to the concentration of E. coli. Hence, E. coli could be detected by the determination of 4-aminophenol. An IrO2–Pd CME, which showed high sensitivity in determination of 4-aminophenol, was prepared as the electro-detector in FIA. The amplified response current of 4-aminophenol obtained at the IrO2–Pd CME was linear with the concentration of E. coli ranging from 2.0 × 102 to 1.0 × 106 cfu/mL, the detection limit of this method to E. coli was 150 cfu/mL and the complete assay could be performed in 3 h.
No preview · Article · Sep 2007 · Electrochemistry Communications
[Show abstract][Hide abstract] ABSTRACT: In this paper, the electro-analysis and spectrophotometric analysis methods were used to study the antibacterial ability of
copper and stainless steel materials. When Escherichia coli (E. coli) and photo-bacteria were used as samples, the antibacterial effect of stainless steel was very weak, while the percentage
of bacteria dying from exposure to metallic copper for 30 min was over 90%. The antibacterial ability of copper has a potential
application in the field of disinfection, food packaging and piping of drinking water.
No preview · Article · Mar 2007 · Frontiers of Chemistry in China