ABSTRACT
The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely "platesomes", which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.
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Solid tumors always exhibit local hypoxia, resulting in the high metastasis and inertness to chemotherapy. Reconstruction of hypoxic tumor microenvironment (TME) is considered a potential therapy compared to directly killing tumor cells. However, the insufficient oxygen delivery to deep tumor and the confronting "Warburg effect" compromise the efficacy of hypoxia alleviation. Herein, we construct a cascade enzyme-powered nanomotor (NM-si), which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy. Catalase (Cat) and glucose oxidase (GOx) are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor (NM), with hexokinase-2 (HK-2) siRNA further condensed (NM-si). The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H
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Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum-curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt-CUR@PSPPN) to facilitate intracellular release and synergistic anti-cancer effects. Pt-CUR@PSPPN was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both and . In addition, Pt-CUR@PSPPN blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt-CUR@PSPPN provided a novel and attractive therapeutic strategy for NSCLC.
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OBJECTIVE@#To evaluate the effects of Celastrus Orbiculatus extracts (COE) on metastasis in hypoxia-induced hepatocellular carcinoma cells (HepG2) and to explore the underlying molecular mechanisms.@*METHODS@#The effect of COE (160, 200 and 240 µ g/mL) on cell viability, scratch-wound, invasion and migration were studied by 3-4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide (MTT), scratch-wound and transwell assays, respectively. CoCl was used to establish a hypoxia model in vitro. Effects of COE on the expressions of E-cadherin, vimentin and N-cadherin were investigated with Western blot and immunofluorescence analysis, respectively.@*RESULTS@#COE inhibited proliferation and metastasis of hypoxia-induced hepatocellular carcinoma cells in a dose-dependent manner (P<0.01). Furthermore, the expression of epithelial-mesenchymal transition (EMT) related markers were also remarkably suppressed in a dose-dependent manner (P<0.01). In addition, the upstream signaling pathways, including the hypoxia-inducible factor 1 α (Hif-1 α) and Twist1 were suppressed by COE. Additionally, the Hif-1 α inhibitor 3-5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), potently suppressed cell invasion and migration as well as expression of EMT in hypoxia-induced HepG2 cells. Similarly, the combined treatment with COE and YC-1 showed a synergistic effect (P<0.01) compared with the treatment with COE or YC-1 alone in hypoxia-induced HepG2 cells.@*CONCLUSIONS@#COE significantly inhibited the tumor metastasis and EMT by suppressing Hif-1 α/Twist1 signaling pathway in hypoxia-induced HepG2 cell. Thus, COE might have potential effect to inhibit the progression of HepG2 in the context of tumor hypoxia.
Subject(s)
Humans , Biomarkers, Tumor , Metabolism , Carcinoma, Hepatocellular , Drug Therapy , Pathology , Celastrus , Chemistry , Cell Hypoxia , Cell Proliferation , Cell Shape , Cobalt , Down-Regulation , Epithelial-Mesenchymal Transition , Hep G2 Cells , Liver Neoplasms , Drug Therapy , Pathology , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Proteins , Metabolism , Plant Extracts , Pharmacology , Therapeutic Uses , Signal TransductionABSTRACT
Immunotherapy has become a highly promising paradigm for cancer treatment. Herein, a chemo-immunotherapy was developed by encapsulating chemotherapeutic drug doxorubicin (DOX) and Toll-like receptor 7 agonist imiquimod (IMQ) in low molecular weight heparin (LMWH)-d--tocopheryl succinate (TOS) micelles (LT). In this process, LMWH and TOS were conjugated by ester bond and they were not only served as the hydrophilic and hydrophobic segments of the carrier, but also exhibited strong anti-metastasis effect. The direct killing of tumor cells mediated by DOX-loaded micelles (LT-DOX) generated tumor-associated antigens, initiating tumor-specific immune responses in combination with IMQ-loaded micelles (LT-IMQ). Furthermore, the blockade of immune checkpoint with programmed cell death ligand 1 (PD-L1) antibody further elevated the immune responses by up-regulating the maturation of DCs as well as the ratios of CD8 CTLs/T and CD4 T/T. Therefore, such a multifunctional strategy exhibited great potential for inhibiting the growth of orthotopic and metastatic breast cancer.
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Objective: To determine the anti-cancer properties of black chokeberry extract on the SK- Hep1 human liver cancer cell line. Methods: MTT cell proliferation assay, wound migration, invasion, zymography and cell cycle were determined after black chokeberry fruit extract treatment. We also measured MMP-2/-9 and MT-1 MMP expression with protein and gene expression levels. Results: We detected four anthocyanins and three phenolic compounds in the black chokeberry by HPLC analysis. Cancer cell growth was inhibited in proportion to the concentration of black chokeberry extracts. In the adhesion test, 100 and 200 μg/mL of black chokeberry extracts decreased the adhesion rate of cancer cells to 87.6% and 75.3%, respectively, when the control group was 100.0%. The 200 μg/mL of black chokeberry extract reduced the MMP-2 and MMP-9 expressions up to 96.8%and 11.3%, respectively. Conclusions: Based on our results, in the SK-Hep1 liver cancer cells, the black chokeberry extract inhibits cancer cell proliferation, adhesion, and migration, ultimately inhibiting cancer metastasis.
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Objective: To determine the anti-cancer properties of black chokeberry extract on the SKHep1 human liver cancer cell line. Methods: MTT cell proliferation assay, wound migration, invasion, zymography and cell cycle were determined after black chokeberry fruit extract treatment. We also measured MMP-2/-9 and MT-1 MMP expression with protein and gene expression levels. Results: We detected four anthocyanins and three phenolic compounds in the black chokeberry by HPLC analysis. Cancer cell growth was inhibited in proportion to the concentration of black chokeberry extracts. In the adhesion test, 100 and 200 μg/mL of black chokeberry extracts decreased the adhesion rate of cancer cells to 87.6％ and 75.3％,respectively, when the control group was 100.0％. The 200 μg/mL of black chokeberry extract reduced the MMP-2 and MMP-9 expressions up to 96.8％and 11.3％, respectively.Conclusions: Based on our results, in the SK-Hep1 liver cancer cells, the black chokeberry extract inhibits cancer cell proliferation, adhesion, and migration, ultimately inhibiting cancer metastasis.
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To study sesquiterpenes with anti-metastasis breast cancer activity from Chloranthus henryi, ten sesquiterpenes ,zedoarofuran (1), chlorajapolide D (2), 4β, 8β-dihydroxy-5α(H)-eudesm-7(11)-en-8, 12-olide (3), curcolonol (4), lasianthuslactone A (5), chlomultin C (6), (1E,4Z)-8-hydroxy-6-oxogermacra-1(10), 4, 7(11) -trieno-12, 8-lactone (7), shizukanolide E (8) , shizukanolide F (9) , 9α-hydroxycurcolonol (10), and five bis-sesquiterpenes, shizukaol B (11), shizukaol C (12) , cycloshizukaol A (13) , sarcandrolide B (14) , henriol A(15), were isolated by using different kinds of column chromatography methods from the ethyl acetate part of Ch.henryi and their structures were identified based on spectroscopic methods. Compounds 2, 8, 9, and 10 were obtained from the genus Chloranthus for the first time. Compounds 2, 5, 8-10, 12,and 14 were obtained from this plant for the first time. Some isolated compounds were subjected to evaluate the anti-metastasis breast cancer activity by using pharmacological methods, and only compounds 4, 11, and 12 were potent active.
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Chondroitin sulfate (CS) is a heterogeneous and negatively charged polysaccharide composed of repeating disaccharideunits, and has many pharmacological activities. CS has been recommended as symptomatic slow acting drugs for osteoarthritis (SYSADOA) in clinical practice. CS is shown to have promising prospect as a potential candidate for anti-metastasis of cancers and as a neurite outgrowth agent for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease characterized by progressive loss of neurons. Moreover, CS is also involved in interaction with virus during its cell entry, wound healing and osteogenesis, and may be a promising drug candidate in these areas. Based on original publications, the research advances of CS in these areas and its applications were reviewed. The possibility of chemoenzymatic synthesis of specific CS chains as potential drugs was also discussed here, which may be used in the treatment of osteoarthritis, anti-metastasis of cancers, and so on.
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Genipin, an aglycone derived from geniposide found in Gardenia jasminoides, is known to be an excellent natural cross-linker, strong apoptosis inducer, and antiviral agent. Although evidence suggests antiviral activity of genipin in several in vitro viral infection systems, there have been few literatures which review antitumor effects of genipin in a variety of in vitro/in vivo models of cancers yet. In this review, we present some of the latest findings in the studies of genipin focusing on antitumor effects and its mechanisms. In brief, genipin inhibits mitochondrial uncoupling protein 2 to increase accumulation of reactive oxygen species, leading to ROS/c-Jun N-terminal kinase-dependent apoptosis of cancer cells. Genipin also increase tissue inhibitors of metalloproteases (MMP), resulting to decrease activities of MMP-2 which plays a key role in metastasis of cancers. Genipin has shown a biphasic effects on cell death and survival in cancer cells as many other plant-derived phytochemicals do. Finally we discuss the potential of genipin as a promosing novel antitumor agent which could be applicable to chemotherapy and/or chemoprevention for cancers.
Subject(s)
Apoptosis , Cell Death , Chemoprevention , Drug Therapy , Gardenia , In Vitro Techniques , Metalloproteases , Neoplasm Metastasis , Phytochemicals , Reactive Oxygen SpeciesABSTRACT
NM23A protein is a kind of multifunctional protein distributed widely in the nature and it exists in almost all the or-ganism and cells. Apart from owning the nucleoside diphosphate kinase activity, NM23A also participates in the physiological process of signal transduction, gene regulation, cell growth and development and so on. NM23A plays important roles in the pa-thology process of the tumor development and metastasis and cen-tral nerve system disease.
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BACKGROUND/OBJECTIVES: D. candidum is a traditional Chinese food or medicine widely used in Asia. There has been little research into the anticancer effects of D. candidum, particularly the effects in colon cancer cells. The aim of this study was to investigate the anticancer effects of D. candidum in vitro and in vivo. MATERIALS/METHODS: The in vitro anti-cancer effects on HCT-116 colon cancer cells and in vivo anti-metastatic effects of DCME (Dendrobium canidum methanolic extract) were examined using the experimental methods of MTT assay, DAPI staining, flow cytometry analysis, RT-PCR, and Western blot analysis. RESULTS: At a concentration of 1.0 mg/mL, DCME inhibited the growth of HCT-116 cells by 84%, which was higher than at concentrations of 0.5 and 0.25 mg/mL. Chromatin condensation and formation of apoptotic bodies were observed in cancer cells cultured with DCME as well. In addition, DCME induced significant apoptosis in cancer cells by upregulation of Bax, caspase 9, and caspase 3, and downregulation of Bcl-2. Expression of genes commonly associated with inflammation, NF-kappaB, iNOS, and COX-2, was significantly downregulated by DCME. DCME also exerted an anti-metastasis effect on cancer cells as demonstrated by decreased expression of MMP genes and increased expression of TIMPs, which was confirmed by the inhibition of induced tumor metastasis in colon 26-M3.1 cells in BALB/c mice. CONCLUSIONS: Our results demonstrated that D. candidum had a potent in vitro anti-cancer effect, induced apoptosis, exhibited anti-inflammatory activities, and exerted in vivo anti-metastatic effects.
Subject(s)
Animals , Humans , Mice , Apoptosis , Asia , Asian People , Blotting, Western , Caspase 3 , Caspase 9 , Chromatin , Colon , Colonic Neoplasms , Down-Regulation , Flow Cytometry , HCT116 Cells , Inflammation , Methanol , Neoplasm Metastasis , NF-kappa B , Up-RegulationABSTRACT
[Objective]To study the effect of Qingre Xiaoji Recipe(QRXJR) on cell transmembrane signaling system’s aniso-compositions:VEGF,CD_(44)V_6,MMPs expressions and tumor metastasis. [Methods]VEGF,CD_(44)V_6,MMPs expressions were determined by immunohistochemical method. [Results]VEGF, CD_(44)V_6,MMPs expression in the group treated by QRXJR were significantly lowered,compared with that in the control group,the difference were significant(P