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The effect of apatinib on the formation of vasculogenic mimicry (VM) was studied in a malignant melanoma cell line. MUM-2B cells cultured in three-dimensional Matrigel were treated with varying concentrations (0, 0.01, 0.05, 0.1, 0.5 μmol/L) of apatinib to test its effect on VM in vitro, followed by MTT proliferation and transwell invasion assays to determine the effect of apatinib on cell proliferation and invasion of MUM-2B cells. In vivo, we used a melanoma cancer model to test the effect of short-term apatinib (100, 200, 300 mg/kg) treatment on VM. Western blotting, immunohistochemistry staining, and CD31-PAS dual staining were performed to assess the expression of VEGFR-2, ERK-1/2, PI3K, and MMP-2, and formation of VM. The results showed apatinib-treated groups formed a lesser number of VM in 3D matrigel, while the cell viability in MTT proliferation assay and the number of migration cells in transwell invasion assay were significantly lower in apatinib-treated groups. In addition, short-term apatinib treatment inhibited angiogenesis, VM formation, and tumor growth in models of melanoma cancer. Mice in apatinib-treated groups showed a markedly reduced expression of VEGFR-2, ERK-1/2, PI3K, and MMP-2. In summary, apatinib could inhibit the expression of VEGFR-2, and downregulate the ERK1/2/PI3K/MMP-2 signaling cascade, which may be one of the underlying mechanisms by which apatinib inhibits angiogenesis and the development of VM in models of melanoma cancer, and restrains the formation of VM by MUM-2B cells. Apatinib shows inhibitory effects on cell proliferation and invasion of MUM-2B cells, which is a close relationship with the VM. [ABSTRACT FROM AUTHOR]

Gefitinib (GEF) is the first epidermal growth factor receptor (EGFR)-targeting agent launched as an anticancer drug. It is an accepted opinion that modifying GEF strong hydrophobicity and poor bioavailability would not only enhance its antitumor effects, but also reduce its side effects. In this study, GEF-loadedpoly(ε-caprolactone)-poly(ethyleneglycol)-poly(ε-caprolactone) (PCEC) -bearing nanoparticles (GEF-NPs) were prepared by a solid dispersion method and characterized. The particle sizes increased with the increase in GEF/PCEC mass ratio in feed. GEF-NPs (10%) were mono-dispersed, smaller than 24 nm, zeta potential was approximately −18 mV, percentage encapsulation and loading, were more than 9% and 92%, respectively, and drug was slowly released but without a biphasic pattern. Microscopy studies of the optimized formulation confirmed that the prepared nanoparticles are spherical in nature. Cytotoxicity results indicated that cell growth inhibition induced by free GEF and GEF-NPs were dose and time dependent. Compared with free GEF, GEF-NPs enhanced antitumor effects, reduced side effects and significantly prolonged survival timein vivo. CD31, ki-67 and EGFR expression were significantly lower in the GEF-NPs group compared with other groups (p< .05). These findings demonstrated that GEF-NPs have the potential to attain superior outcomes and to overcome complications such as organs toxicity, therapeutic resistance and disease relapse. [ABSTRACT FROM AUTHOR]

The purpose of this study was to prepare endostatin-loaded chitosan nanoparticles (ES-NPs) and evaluate their antitumor effect when combined with paclitaxel (PTX) on Lewis lung carcinoma (LLC) mouse xenografts. ES-NPs were prepared by ionic cross-linking. Characterization of the ES-NPs included size distribution, drug-loading efficiency (DL), and encapsulation efficiency (EE). Anin vitrorelease test was also used to determine the release behavior of the ES-NPs. A subcutaneous LC xenograft model of C57BL/6J mice was established. The mice were randomly divided into six groups: control (0.9% NaCl), ES, PTX, ES-NPs, ES + PTX, and ES-NPs + PTX. The tumor volume was dynamically measured for the duration of the experiment. Immunohistochemistry was performed to determine the Ki-67 and microvascular density (MVD) in each group. Serum vascular endothelial growth factor (VEGF) and ES levels were determined by enzyme-linked immunosorbent assay (ELISA). ES-NPs were successfully synthesized and had suitable size distribution and high EE. The NPs were homogenously spherical and exhibited an ideal release profilein vitro. In vivo, tumor growth was significantly inhibited in the ES-NPs + PTX group. The tumor inhibitory rate was significantly higher in the ES-NPs + PTX group than in the other groups (p < .05). The results of the immunohistochemical assay and ELISA confirmed that ES-NPs combined with PTX had a strong antiangiogenic effect. ES-NPs can overcome the shortcomings of free ES, such as short retention time in circulation, which enhances the antitumor effect of ES. The antitumor effect was more pronounced when treatment included PTX and ES-loaded NPs. [ABSTRACT FROM AUTHOR]

In this study, we investigatedin vivoradiosensitizing effects of a gel-based dual drug delivery system (DDS) (PECE/DDP + mPEG-PCL/PTX, or PDMP) in a cervical cancer model, and determined its possible mechanisms of action. A xenograft cervical cancer model was used to investigate the radio sensitization effect of PDMP. Mice underwent paclitaxel (PTX) + cisplatin (DDP), PECE, or PDMP treatment followed by single radiation doses ranging from 0 Gy to 20 Gy. Radio sensitization was analyzed by tumor regrowth delay (TGD). The sensitization enhancement ratio (SER) was calculated by the doses needed to yield TGD when using radiation treatment alone and when using radiation plus drug treatment. The impact of irradiation and drugs on TGD was determined, and an optimum radiation dose was chosen for further evaluation of radio sensitizing effects. The data showed that PDMP yielded the highest radio sensitization (SER was 1.3) and a radiation dose of 12 Gy was chosen for further investigation. PDMP + radiotherapy treatment was most effective in inhibiting tumor growth, prolonging survival time, decreasing expression of CD31, CD133, and aldehyde dehydrogenase 1 (ALDH1), inducing G2/M phase arrest, apoptosis, and expression of Ataxia telangiectasia mutated (ATM) and histone H2AX phosphorylation (γ-H2AX). Thus, our data indicated that PDMP is a promising anti-tumor and radio sensitization reagent for the treatment of cervical carcinoma. [ABSTRACT FROM AUTHOR]

The purpose of this study was to prepare ES-loaded chitosan nanoparticles (ES-NPs) and evaluate the antitumor effect of these particles on the Lewis lung cancer model. ES-NPs were prepared by a simple ionic cross-linking method. The characterization of the ES-NPs, including size distribution, zeta potential, loading efficiency and encapsulation efficiency (EE), was performed. Anin vitrorelease test was also used to determine the release behavior of the ES-NPs. Cell viability and cell migration were assayed to detect thein vitroantiangiogenic effect of ES-NPs. In order to clarify the antitumor effect of ES-NPsin vivo, the Lewis lung cancer model was used. ES-NPs were successfully synthesized and shown to have a suitable size distribution and high EE. The nanoparticles were spherical and homogeneous in shape and exhibited an ideal releasing profilein vitro. Moreover, ES-NPs significantly inhibited the proliferation and migration of human umbilical vascular endothelial cells (HUVECs). Thein vivoantiangiogenic activity was evaluated by ELISA and immunohistochemistry analyses, which revealed that ES-NPs had a stronger antiangiogenic effect for reinforced anticancer activity. Indeed, even the treatment cycle in which ES-NPs were injected every seven days, showed stronger antitumor effect than the free ES injected for 14 consecutive days. Our study confirmed that the CS nanoparticle is a feasible carrier for endostatin to be used in the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

This study prepared a composite scaffold composed of curcumin and poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymer using coelectrospinning technology. Incorporation of curcumin into the polymeric matrix had an obvious effect on the morphology and dimension of PCEC/curcumin fibers. The results of in vitro anti-oxidant tests and of the cytotoxicity assay demonstrated that the curcumin-loaded PCEC fibrous mats had significant anti-oxidant efficacy and low cytotoxicity. Curcumin could be sustainably released from the fibrous scaffolds. More importantly, in vivo efficacy in enhancing wound repair was also investigated based on a full-thickness dermal defect model for Wistar rats. The results indicated that the PCEC/curcumin fibrous mats had a significant advantage in promoting wound healing. At 21 days post-operation, the dermal defect was basically recovered to its normal condition. A percentage of wound closure reached up to 93.3 ± 5.6% compared with 76.9 ± 4.9% of the untreated control ( p < 0.05). Therefore, the as-prepared PCEC/curcumin composite mats are a promising candidate for use as wound dressing. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 533-542, 2014. [ABSTRACT FROM AUTHOR]

The molecule 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid (danshensu), a herbal preparation used in traditional Chinese medicine, has been found to possess potential antitumor and anti-angiogenesis effects. The aim of the present study was to investigate the efficacy of the combination of radiation therapy (RT) with danshensu in the treatment of Lewis lung carcinoma (LLC) xenografts, whilst exploring and evaluating the mechanism involved. In total, 8-week old female C57BL/6J mice were randomly assigned into 3 groups to receive: RT, RT + cisplatin and RT + danshensu, respectively, when LLC reached 100-150 mm 3 . Each group was divided into 7 subgroups according to the different irradiation doses that were administered. Tumor growth curves were created and the sensitization enhancement ratios of the drugs were calculated. The experiment was then repeated, and the 4 groups of tumor-bearing mice were treated with natural saline, danshensu, RT + danshensu and RT, respectively. The mice were sacrificed on day 7, and tumor tissue and blood were collected to determine microvessel density, the expression of proangiogenic factors, and the levels of blood thromboxane B 2 and 6-keto-prostaglandin-F1α. Tumor hypoxia was also detected using in vivo fluorescence imaging. With respect to LLC xenografts, treatment with danshensu + RT significantly enhanced the effects of tumor growth inhibition (P<0.05). Furthermore, tumor vasculature was remodeled and microcirculation was improved, which significantly reduced tumor hypoxia (P<0.05). The present study demonstrated that danshensu significantly enhanced the radioresponse of LLC xenografts in mice. The mechanism involved may be associated with the alleviation of tumor cell hypoxia following treatment with danshensu + RT, caused by the improvement of tumor microcirculation and the remodeling of tumor vasculature.

Treatment for cancer can induce a series of secreted factors into the tumor microenvironment, which can affect cancer progression. Wingless-type MMTV (mouse mammary tumor virus) integration site 16B (WNT16B) is a new member of the WNT family and has been reported to play growth-related roles in previous studies. In this study, we found WNT16B could be expressed and secreted into the microenvironment by human ovarian fibroblasts after DNA damage-associated treatment, including chemotherapy drugs and radiation. We also demonstrated that fibroblast-derived WNT16B could result in accumulation of β-catenin in dendritic cells and secretion of interleukin-10 (IL-10) and transforming growth factor beta (TGF-β), which contributed to the differentiation of regulatory T cells in a co-culture environment. These results shed light on the roles of WNT16B in immune regulation, especially in regard to cancer treatment.

Post-operative peritoneal adhesions are serious consequences of abdominal or pelvic surgery and cause severe bowel obstruction, chronic pelvic pain and infertility. In this study, a novel nano-hydrogel system based on a monomethoxy poly(ethylene glycol)-poly(lactic acid) (MPEG-PLA) di-block copolymer was studied for its ability to prevent abdominal adhesion in rats. The MPEG-PLA hydrogel at a concentration of 40% (w/v) was injected and was able to adhere to defect sites at body temperature. The ability of the hydrogel to inhibit adhesion of post-operative tissues was evaluated by utilizing a rat model of abdominal sidewall-cecum abrasion. It was possible to heal wounded tissue through regeneration of neo-peritoneal tissues ten days after surgery. Our data showed that this hydrogel system is equally as effective as current commercialized anti-adhesive products.

Scaffolds for bone tissue engineering applications should have suitable degradability in favor of new bone ingrowth after implantation into bone defects. In this study, degradation behavior of polyurethane composites composed of triblock copolymer poly(caprolactone)-poluronic-poly(caprolactone) (PCL-Pluronic-PCL, PCFC) and nanohydroxyapatite (n-HA) was investigated. The water contact angle and water absorption were measured to reveal the effect of n-HA content on the surface wettability and swelling behavior of the n-HA/PCFC composites, respectively. The weight loss in three degradation media with pH value of 4.0, 7.4, and 9.18 was also studied accordingly. Fourier transform infrared analysis, differential scanning calorimeter, X-ray diffraction, thermal-gravimetric analysis, and scanning electron microscopy were used to investigate the change of chemical structure and micromorphology after the n-HA/PCFC composite with 30% HA was degraded for different time intervals. Meanwhile, in vivo degradation was conducted by subcutaneous implantation. The weight loss and morphology change during observation periods were also studied., (© 2013 Wiley Periodicals, Inc.)

Radiotherapy is a crucial treatment for cervical cancer, the second most common type of cancer in women worldwide. In this study, we investigated the effects of CXC chemokine ligand 10 (CXCL10) gene therapy combined with radiotherapy on cervical cancer using HeLa cells. TUNEL assay revealed that the apoptotic rate in the combined treatment of CXCL10 gene therapy and radiotherapy was greatly increased compared with that of CXCL10 or radiotherapy alone. Flow cytometry showed that CXCL10 overexpression in HeLa cells resulted in a prolonged G1 phase and shortened S phase at 72 h post-transfection. Western blot analysis revealed that p27(Kip1) was up-regulated in CXCL10-treated HeLa cells; however, cyclin E was down-regulated. These results indicate that the combination of CXCL10 gene therapy and radiotherapy is an effective strategy for the growth suppression of HeLa cells, and that CXCL10 enhances the radiotherapy effects through cell cycle redistribution. Our data provide new insight into the treatment of cervical carcinoma, involving an effective combination of gene therapy and radiotherapy against tumors.