Real-time monitoring the staged interactions between cationic surfactants and a phospholipid bilayer membrane.

The cationic surfactant-lipid interaction directs the development of novel types of nanodrugs or nanocarriers. The membrane action of cationic surfactants also has a wide range of applications. In this work, combining a photo-voltage transient method with the traditional dynamic giant unilamellar vesicle (GUV) leakage assay and molecular dynamics (MD) simulations, we monitored the molecular actions of a representative cationic surfactant, tetradecyl trimethyl ammonium bromide (TTAB), in a wide concentration range (i.e., 0.5 µM-10 mM), on a phospholipid bilayer membrane in real time. With low concentrations (e.g., ≤10 µM), TTAB performed a three-stage acting process, including the structural-disturbance-dominated, adsorption-dominated, and dynamic equilibrium stages. At higher concentrations (e.g., ≥100 µM), this process was accelerated to two stages. Furthermore, TTAB induced deformation and even rupture of the membrane, due to the asymmetric disturbance of surfactant molecules on the two leaflets of a bilayer. All these disturbances induced membrane permeabilization, and the times at which these transitions occurred are given. This work provides information on time and molecular mechanism during the membrane actions of cationic surfactants, and provides a simple and real-time method in studying the dynamic processes at the membrane interface.

Chemically Modified Surface Having a Dual-Structured Hierarchical Topography for Controlled Cell Growth.

This report describes a technique for fabricating dual-structured hierarchical surface topography on the surface of polydimethylsiloxane (PDMS) films through simply replicating prefabricated patterns and wrinkling PDMS films. To enhance the biocompatibility of PDMS films, we synthesize a biocompatible dopamine-glycopolymer, which is utilized to modify the chemical feature of the PDMS surface. Dopamine component in this copolymer is introduced for the formation of a carbohydrate layer on the surface of PDMS films because of its excellent adhesion. The carbohydrate component in this copolymer enhances the interactions between cells and PDMS films. We investigate the influence of the chemical and topographical surface properties of the extracellular matrix on fibroblast cell growth. The coupling of the dopamine-glycopolymer coating and hierarchical topography produces the best induction effect on the alignment of cells.

One-pot synthesis of silicon based nanoparticles with incorporated phthalocyanine for long-term bioimaging and photo-dynamic therapy of tumors.

Combining the merits of delivery vectors with drug molecules is one of the key directions for development of efficient cancer monitoring and treatment techniques. In this work, a novel type of silicon based composite nanoparticles (NPs) with incorporated hydrophobic phthalocyanine molecules (Pc) was synthesized via a facile one-pot method. The as-synthesized Pc@Si NPs, with a small size of 4.2 ± 0.8 nm, have excellent dispersibility in water and good biocompatibility with cells, in addition to favorable photoluminescence and robust photostability even in cells. Moreover, the Pc@Si NPs show significant in vitro cancer cell killing and in vivo tumor inhibiting abilities upon near-infrared light exposure, due to the photodynamic therapy (PDT) effect of Pc. This work develops an efficient fluorescent PDT drug carrier; moreover, the facile one-pot synthesis strategy may be used generally to prepare silicon-based composite NPs incorporated with diverse hydrophobic drugs/diagnostic molecules for a wide range of biomedical applications.

Plasmon-enhanced fluorescence imaging with silicon-based silver chips for protein and nucleic acid assay.

Metal-enhanced fluorescence shows great potential for improving the sensitivity of fluoroscopy, which has been widely used in protein and nucleic acid detection for biosensor and bioassay applications. In comparison with the traditional glass-supported metal nanoparticles (MNPs), the introduction of a silicon substrate has been shown to provide an increased surface-enhanced Raman scattering (SERS) effect due to the coupling between the MNPs and the semiconducting silicon substrate. In this work, we further study the fluorescence-enhanced effect of the silicon-supported silver-island (Ag@Si) plasmonic chips. In particular, we investigate their practical application of improving the traditional immunoassay such as the biotin-streptavidin-based protein assay and the protein-/nucleic acid-labeled cell and tissue samples. The protein assay shows a wavelength-dependent enhancement effect of the Ag@Si chip, with an enhancement factor ranging from 1.2 (at 532 nm) to 57.3 (at 800 nm). Moreover, for the protein- and nucleic acid-labeled cell and tissue samples, the Ag@Si chip provides a fluorescence enhancement factor of 3.0-4.1 (at 800 nm) and a significant improvement in the signal/background ratio for the microscopy images. Such a ready accommodation of the fluorescence-enhanced effect for the immunoassay samples with simple manipulations indicates broad potential for applications of the Ag@Si chip not only in biological studies but also in the clinical field.

Oroxin A inhibits breast cancer cell growth by inducing robust endoplasmic reticulum stress and senescence.

Breast cancer is a major cause of cancer death among women. Although various anticancer drugs have been used in clinics, drugs that are effective against advanced and metastatic breast cancer are still lacking and in great demand. In this study, we found that oroxin A, an active component isolated from the herb Oroxylum indicum (L.) Kurz, effectively inhibited the growth of human breast cancer cells MDA-MB-231 and MCF7 by inducing endoplasmic reticulum (ER) stress-mediated senescence. Oroxin A caused breast cancer cell cycle arrest at the G2/M stage, and reorganization of microtubules and actin cytoskeleton accompanied by a decrease in cellular mitosis. ER-specific probe ER-Tracker Red and confocal microscope imaging showed that ER-Tracker Red-positive cells increased in an oroxin A dosage-dependent manner. In addition, oroxin A increased cell population with high ß-Gal activity and SAHF-positive staining; these data suggest that oroxin A induces breast cancer cell ER stress and senescence. Mechanistic studies showed that oroxin A led to a significant increase in intracellular reactive oxygen species levels, promoted expression of ER stress markers ATF4 and GRP78, and increased the phosphorylation of a key stress-response signaling protein p38, resulting in an ER stress-mediated senescence. Taken together, our data indicate that oroxin A exerts its antibreast cancer effects by inducing ER stress-mediated senescence, activating the key stress p38 signaling pathway, and increasing key ER stress genes ATF4 and GRP78 expression levels.

Unraveling the novel anti-osteosarcoma function of coptisine and its mechanisms.

Uncontrolled cell proliferation and robust angiogenesis play critical roles in osteosarcoma growth and metastasis. In this study we explored novel agents derived from traditional Chinese medicinal herbs that potently inhibit osteosarcoma growth and metastasis. Coptisine, an active component of the herb Coptidis rhizoma, markedly inhibited aggressive osteosarcoma cell proliferation. Coptisine induced cell cycle arrest at the G0/G1 phase through downregulation of CDK4 and cyclin D1 expression and effectively suppressed tumor growth in a xenografted mouse model. Coptisine significantly impeded osteosarcoma cell migration, invasion, and capillary-like network formation by decreasing the expression of VE-cadherin and integrin ß3, and diminishing STAT3 phosphorylation. Coptisine significantly elevated blood erythrocyte and hemoglobin levels while still remaining within the normal range. It also moderately increased white blood cell and platelet counts. These data suggest that coptisine exerts a strong anti-osteosarcoma effect with very low toxicity and is a potential anti-osteosarcoma drug candidate.

Glycopolymer-coated iron oxide nanoparticles: shape-controlled synthesis and cellular uptake.

Carbohydrates are involved in different cellular recognition events, and glycopolymers with carbohydrate side chains are currently being applied in many fields, with much potential for disease treatment. The aggregation shape has obvious effects on the nanoparticle-cell interaction and is therefore important for the applications of glycopolymers in biological systems. The synthesis of well-defined glyco-nanoparticles, especially non-spherical ones, is challenging work. Herein, iron oxide nanoparticles with different shapes (spindle and cubic-like) were first obtained and used as a core that was coated with dopamine methacrylamide (DMA) via catecholic chemistry for the introduction of vinyl groups. RAFT-synthesized glycopolymers were then conjugated to the DMA-coated iron oxide nanoparticles via a thiol-ene coupling reaction. By combining the convenience of inorganic nanoparticle shape control, biomimic catecholic chemistry, and efficient thiol-ene reaction, glycopolymer-decorated nanoparticles were easily obtained. Glyco-nanoparticles with variable shapes are stable in serum and exhibit shape-dependent cell uptake behaviors as well as enhanced activity toward specific lectins. The fabrication of biologically active non-spherical nanoparticles will be beneficial for both fundamental research on nanoparticle-cell interaction and related applications for disease treatment.

Tumour vasculogenic mimicry is associated with poor prognosis of human cancer patients: a systemic review and meta-analysis.

BACKGROUND: Vasculogenic mimicry (VM) has been reported in various malignant tumours and is known to play an important role in cancer progression and metastasis. However, the impact of VM on the overall survival of human cancer patients remains controversial. The goal of this study was to evaluate whether VM is associated with 5-year survival of human cancer patients. METHODS: Twenty-two eligible clinical studies with data on both tumour cell-dominant VM and the 5-year survival of 3062 patients involved in 15 types of cancers were pooled in the meta-analysis. RESULTS: The 5-year overall survival of VM-positive and -negative cancer patients was 31% and 56%, respectively. The relative risk (RR) of the 5-year survival of VM-positive patients was significantly higher than that of VM-negative cases (RR=1.531; 95% confidence interval (CI): 1.357-1.726; P<0.001). Notably, metastatic melanoma patients demonstrated a higher VM rate (45.3%) than patients with primary melanoma (23.1%) and showed worse 5-year survival, suggesting that VM contributes to tumour metastasis and poor prognosis in cancer patients. Subgroup analysis indicated that a poor 5-year survival was significantly associated with eight types of VM-positive malignant tumours, such as lung, colon, liver cancers, sarcomas and melanoma; but was not associated with the seven other types of cancers, such as prostate cancer. Heterogeneity and publication biases were found among the 22 studies, mainly due to the divergent characteristics of cancers and extremely low survival rate in six types of malignant tumours. CONCLUSION: VM-positive cancer patients show a poor 5-year overall survival compared with VM-negative malignant tumour cases, particularly in metastatic cancer.

Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity.

Uncontrolled tumor cell proliferation and robust neovascularization are prominent features of aggressive ovarian cancers. Although great efforts in anti-ovarian cancer therapy have been made in the past 4 decades, the 5-year survival rates for ovarian cancer patients are still poor, and effective drugs to cure ovarian cancer patients are absent. In this study, we evaluated the anti-cancer effects of lycorine hydrochloride (LH), a novel anti-ovarian cancer agent, using the highly-invasive ovarian cancer cell line, Hey1B, as a model. Our data showed that LH effectively inhibited mitotic proliferation of Hey1B cells (half maximal inhibitory concentration=1.2µM) with very low toxicity, resulting in cell cycle arrest at the G2/M transition through enhanced expression of the cell cycle inhibitor p21 and marked down-regulation of cyclin D3 expression. Moreover, LH suppressed both the formation of capillary-like tubes by Hey1B cells cultured in vitro and the ovarian cancer cell-dominant neovascularization in vivo when administered to Hey1B-xenotransplanted mice. LH also suppressed the expression of several key angiogenic genes, including VE-cadherin, vascular endothelial growth factor, and Sema4D, and reduced Akt phosphorylation in Hey1B cells. These results suggest that LH selectively inhibits ovarian cancer cell proliferation and neovascularization and is a potential drug candidate for anti-ovarian cancer therapy.

Columbamine suppresses the proliferation and neovascularization of metastatic osteosarcoma U2OS cells with low cytotoxicity.

Osteosarcoma is one of the most common malignant bone tumors in children and adolescents. Although extensive efforts have been made in anti-osteosarcoma therapy in recent decades, there are no effective low-toxicity drugs for treating patients with metastatic osteosarcoma. Hence, potent anti-metastatic osteosarcoma drugs are highly desired. In this study, we explored novel small molecular anti-metastatic osteosarcoma agents and found that columbamine (COL), an active component of the herb Coptis chinensis, inhibited the proliferation and neovascularization of metastatic osteosarcoma U2OS cells. COL effectively suppressed U2OS cell proliferation in vitro with an IC(50) of 21.31±0.38µM, with low cytotoxicity. Mechanistic studies revealed that COL induces cell cycle arrest at the G2/M transition, which is associated with attenuating CDK6 gene expression and diminishing STAT3 phosphorylation. COL did not significantly promote U2OS cell apoptosis at any of the dosages tested. Additionally, COL inhibited U2OS cell-mediated neovascularization, which was accompanied by the down-regulation of matrix metalloproteinase (MMP) 2 expression and reduction of cell migration, adhesion, and invasion. Taken together, our data show that COL exerts anti-proliferative and anti-vasculogenic effects on metastatic human osteosarcoma U2OS cells with low toxicity. These results warrant further investigation of COL as a potential anti-osteosarcoma and anti-cancer drug.

Lycorine hydrochloride inhibits metastatic melanoma cell-dominant vasculogenic mimicry.

Melanoma cells actively participate in tumor angiogenesis and vasculogenic mimicry. However, anti-angiogenic therapy in patients with melanoma has not shown a significant survival gain. Thus, new anti-melanoma angiogenic and vasculogenic drugs are highly desired. Using the metastatic melanoma cell line C8161 as a model, we explored melanoma vasculogenic inhibitors and found that lycorine hydrochloride (LH) effectively suppressed C8161 cell-dominant formation of capillary-like tubes in vitro and generation of tumor blood vessels in vivo with low toxicity. Mechanistic studies revealed that LH markedly hindered expression of VE-cadherin in C8161 cells, but did not affect expression of six other important angiogenic and vasculogenic genes. Luciferase assays showed that LH significantly impeded promoter activity of the VE-cadherin gene in a dose-dependent manner. Together, these data suggest that LH inhibits melanoma C8161 cell-dominant vasculogenic mimicry by reducing VE-cadherin gene expression and diminishing cell surface exposure of the protein.

Novel function of scutellarin in inhibiting cell proliferation and inducing cell apoptosis of human Burkitt lymphoma Namalwa cells.

Anti-lymphoma therapy continues to present a major challenge. Even though cytotoxic therapy, immunotherapy and molecularly targeted therapy have been used in the clinic to treat the disease, effective anti-lymphoma drugs are still needed. In this study, we explored novel anti-lymphoma agents and found that scutellarin, an active component of a traditional Chinese medicinal herb Erigeron breviscapus, executed an anti-lymphoma effect. Scutellarin diminished the proliferation of B-lymphoma Namalwa cells in vitro and inhibited lymphoma growth in Namalwa cell-xenotransplanted mice without obvious toxicity. A mechanism study showed that scutellarin at doses of less than 10 µM induced cell cycle arrest at G0/G1 transition without the induction of cell apoptosis, which was accompanied by down-regulation of cyclin D1 and CDK4 expression. In contrast, scutellarin at concentrations of 15 µM or above promoted Namalwa cell apoptosis, which was partially associated with the activation of caspases. These results suggest that scutellarin is a new potential anti-lymphoma candidate.