Improved Antitumor Efficacy of a Dextran-based Docetaxel-coupled Conjugate against Triple-Negative Breast Cancer.

BACKGROUND: Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations. OBJECTIVE: This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer. METHODS: DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice. RESULTS: The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8 ± 5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triplenegative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects. CONCLUSION: This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.

Influence of unsaturated fatty acids on the antitumor activity of polymeric conjugates grafted with cabazitaxel against prostate cancer.

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.

Polysaccharide dextran-based conjugate for selective co-delivery of two synergistic drugs docetaxel and docosahexaenoic acid to tumor cells.

Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran-DHA-DTX. The single-drug conjugates dextran-DHA and dextran-DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran-Cy7.5 and dextran-DHA-Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran-DHA-DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran-DHA-Cy7.5. Importantly, the dual-drug conjugate dextran-DHA-DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran-DTX and dextran-DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran-DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.

A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues.

Purpose: Most chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed. Methods: A bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models. Results: The dextran-docosahexaenoic acid (DHA)- docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran-DHA-DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice. Conclusion: These dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.

Complete regression of xenografted breast tumors by dextran-based dual drug conjugates containing paclitaxel and docosahexaenoic acid.

In this study, a novel carboxymethyl dextran (CMD)-based dual drug delivery system that delivering two water insoluble drugs to tumor sites was developed and evaluated for anticancer activities. Paclitaxel (PTX) and docosahexaenoic acid (DHA) were covalently coupled with CMD to generate CMD-DHA-PTX conjugate S and conjugate L with different linkers containing amino acids Gly-Gly or Lys-Gly-Gly, respectively. Both conjugates possessed high PTX loading contents and enhanced water solubility, as well as the ability of being self-assembled into nanoparticles with the nanoparticle size ranged from 88.7 nm to 94.7 nm. These two conjugates released free PTX continuously in plasma and cancer cells. The conjugate S exhibited improved pharmacokinetic parameters and higher distribution extent in tumor sites than the parent PTX, Abraxane and the conjugate L. The antitumor efficacy of these two conjugates outperformed parent PTX formulation and Abraxane in nude mice bearing breast cancer cells MCF-7. More importantly, the conjugate S treatment eliminated all the xenograft tumors without causing any mice body weight loss in mice model. This study revealed that the dextran-based dual drug conjugates may represent an effective and innovative way to deliver anticancer agents to a variety of tumors.

The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid.

Docetaxel (DTX) has been widely used for the treatment of many types of cancer. However, DTX is poorly water-soluble and commercial DTX is formulated in non-ionic surfactant polysorbate 80 and ethanol, thereby leading to hypersensitivity and serious side effects. Herein, a polymer dual drug conjugate was synthesized by coupling DTX and docosahexaenoic acid (DHA) with bifunctionalized dextran. The polysaccharide conjugate dextran-DHA-DTX possessed high water solubility and was self-assembled into nanoparticles with a diameter of 98.0 ± 6.4 nm. Pharmacokinetic and biodistribution studies showed that the dextran-DHA-DTX dual drug conjugate not only had significantly prolonged blood circulation but was also selectively accumulated in the tumor with reduced drug distribution in normal tissues. The conjugate exhibited a superior therapeutic effect in both xenograft nude mice models without causing any systemic side effects. Notably, the conjugate nearly eliminated all xenograft tumors in nude mice bearing breast cancer cells MCF-7. This study revealed that the dextran-based dual drug delivery system may provide an effective strategy to selectively deliver DTX to tumor sites.

Tripartite motif-containing 25 facilitates immunosuppression and inhibits apoptosis of glioma via activating NF-κB.

As a crucial tumor type of the central nervous system, gliomas are characterized by a dismal prognosis. Tripartite motif-containing 25 (TRIM25), an essential E3 ubiquitin ligase, participates in various biological processes. This study sought to demonstrate its functional role in gliomas. Data obtained from publicly available databases - including The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Repository for Molecular Brain Neoplasia Data (REMBRANDT) - were employed. TRIM25 expression pattern and its association with different clinical characteristics were analyzed. Kaplan-Meier analysis was utilized to compare different TRIM25 expressions with glioma patients' survival. Subsequently, we performed bioinformatic analyses to investigate the biological functions of TRIM25, which were further validated by in vitro experiments, CIBERSORT algorithm, and ESTIMATE evaluation. TRIM25 expression was upregulated in glioma patients and can predict an unfavorable prognosis. Bioinformatic results indicated the involvement of TRIM25 in apoptosis and immune regulation. TRIM25 was associated with programmed death-ligand 1 (PD-L1) related and macrophage-induced immune suppression in gliomas. Meanwhile, silencing TRIM25 promoted apoptosis in glioma cells, which is attributed to its regulation of NF-κB. Therefore, TRIM25 contributed to the glioma malignant progression and suppressive immune microenvironments via NF-κB activation, which may play a therapeutic role in gliomas.

Thymic Immunosuppressive Pentapeptide (TIPP) Shown Anticancer Activity in Breast Cancer and Chronic Myeloid Leukemia Both In Vitro and In Vivo.

AIM: Being the common cause and major burden of deaths globally, timely cancer management is crucial. BACKGROUND: Thymic immunosuppressive pentapeptide (TIPP) is a novel pentapeptide originally obtained from calf thymic immunosuppressive extract. Previously, TIPP has been proved to suppress the allergic and inflammatory responses in allergic mice via blocking MAP kinases/NF-κB signaling pathways. OBJECTIVE: In this study, in vitro anticancer activity of TIPP was tested on two different types of cancers using MCF-7 and K562 cell lines. METHODS: Tumor xenograft models for breast cancer and chronic myeloid leukemia were designed. In vivo anticancer activity of TIPP was investigated on both cancer types. The liver and tumor tissues of the mice were preserved for immunohistochemistry analysis. RESULTS: In vitro anticancer activity of TIPP showed significant inhibition on cell viability of both breast cancer and chronic myeloid leukemia. In vivo anticancer effect of TIPP in both types of cancer models further proved the potent anticancer nature of TIPP. Immunohistochemistry analysis assured that TIPP is a safe drug for normal organs such as the liver. CONCLUSION: Our present study revealed that TIPP is a potent anticancer drug and an important treatment option for various diseases. Further work is needed to test the flexible and proficient activity of the novel peptide.

Cisplatin enhances protein O­GlcNAcylation by altering the activity of OGT, OGA and AMPK in human non­small cell lung cancer cells.

O­GlcNAcylation is a dynamic and reversible post­translational modification of proteins that is modulated by O­GlcNAc transferase (OGT) and O­GlcNAcase (OGA). Alterations in the protein expression of O­linked ß­N­acetylglucosamine (O­GlcNAc) can be induced by multiple factors. However, little is known of the effects of chemotherapeutic agents on O­GlcNAcylation and the relevant molecular mechanisms in cancer cells. In the present study, to investigate whether cisplatin alters protein O­GlcNAcylation and to explore whether protein O­GlcNAc modification affects the antitumor activity of cisplatin, experiments were performed in vitro and in vivo. The results indicated that cisplatin treatment resulted in an enhancement of global protein O­GlcNAc levels in the H1299, Hep G2 and MCF­7 cells in vitro and in vivo. Cisplatin upregulated the protein and mRNA expression levels of OGT and OGA in H1299 cells. Moreover, cisplatin induced the significant enhancement of the enzymatic activity of OGT in H1299 cells. On the contrary, the activation of OGA decreased in response to cisplatin exposure in H1299 cells. Cisplatin inhibited the activity of AMP­activated protein kinase (AMPK) by decreasing the AMP/ATP ratio. The present study also revealed that the decreased AMPK activation inhibited glutamine­fructose­6­phosphate aminotransferase (isomerizing) 1 (GFAT1) phosphorylation and subsequently promoted the activity of GFAT1. Cisplatin­induced GFAT1 activation elevated the production of the donor substrate, uridine 5­diphospho­N­acetylglucosamine (UDP­GlcNAc). However, alterations in the O­GlcNAc levels by the inhibition of OGT and OGA did not affect the sensitivity of lung cancer cells to cisplatin. On the whole, the present study demonstrates that cisplatin enhances protein O­GlcNAcylation by altering the activity of OGT, OGA and AMPK in vitro and in vivo.

A sonosensitiser-based polymeric nanoplatform for chemo-sonodynamic combination therapy of lung cancer.

BACKGROUND: Lung cancer is the most common type of tumour worldwide. Its relative lethality is considerably high. However, since the tumour tissues are located deep within the human body, traditional technologies, such as photodynamic therapy, do not have the desired effect. Sonosensitisers can penetrate deeply into tissues, and sonodynamic therapy (SDT) effectively inhibits tumours by generating reactive oxygen species. Ultrasound can also penetrate deeply, with a favourable tumour inhibition effect. RESULTS: A redox/ultrasound-responsive Rhein-chondroitin sulphate-based nano-preparation encapsulating docetaxel was fabricated. The nanoparticles displayed increased cellular uptake with quick drug release, good stability, and a monodispersed form in the physiological environment. Rhein induced apoptosis and altered mitochondrial membrane potential, which enhanced the expression of apoptosis-related proteins. SDT inhibited the metastasis and angiogenesis of cancer cells and activated anti-tumour capacity by reducing the expression of M2 macrophages. CONCLUSIONS: The potential of Rhein for SDT was demonstrated. Production of reaction oxygen species was markedly enhanced after ultrasound treatment. The nanoplatform enhanced the synergistic anti-tumour effects of SDT and chemotherapeutic efficacy. The approach was biocompatibility. The findings could inform investigations of chemo-SDT for different cancers.

Cascade synthesis of uridine-5'-diphosphate glucuronic acid by coupling multiple whole cells expressing hyperthermophilic enzymes.

BACKGROUND: Enzymatic glycan synthesis has leapt forward in recent years and a number of glucuronosyltransferase (EC 2.4.1.17) have been identified and prepared, which provides a guide to an efficient approach to prepare glycans containing glucuronic acid (GlcA) residues. The uridine 5'-diphosphate (UDP) activated form, UDP-GlcA, is the monosaccharide donor for these glucuronidation reactions. RESULTS: To produce UDP-GlcA in a cost-effective way, an efficient three-step cascade route was developed using whole cells expressing hyperthermophilic enzymes to afford UDP-GlcA from starch. By coupling a coenzyme regeneration system with an appropriate expression level with UDP-glucose 6-dehydrogenase in a single strain, the cells were able to meet NAD+ requirements. Without addition of exogenous NAD+, the reaction produced 1.3 g L-1 UDP-GlcA, representing 100% and 46% conversion of UDP-Glc and UTP respectively. Finally, an anion exchange chromatography purification method was developed. UDP-GlcA was successfully obtained from the cascade system. The yield of UDP-GlcA during purification was about 92.0%. CONCLUSIONS: This work built a de novo hyperthermophilic biosynthetic cascade into E. coli host cells, with the cells able to meet NAD+ cofactor requirements and act as microbial factories for UDP-GlcA synthesis, which opens a door to large-scale production of cheaper UDP-GlcA.

Pluronic F127-functionalized molybdenum oxide nanosheets with pH-dependent degradability for chemo-photothermal cancer therapy.

Traditional cancer therapies carry a risk of serious side effects and toxicity. Developing an alternative treatment modality that is highly effective, has low toxicity and is noninvasive is urgently required. Here, we exploited molybdenum oxide (MoOx) nanosheets as a drug carrier and degradable photothermal agent to provide a chemo-photothermal combination cancer therapy. The MoOx nanosheets were synthesized by a one-pot hydrothermal method and then modified with pluronic F127 to improve physiological stability and biocompatibility. The F127-modified nanosheets (MoOX@F127) showed ultrahigh drug loading efficiency (DLE) of doxorubicin (DOX) (DLE%; 65%, W(load DOX)/[W(load DOX) + WMoOx@F127]), strong near-infrared (NIR) absorption and desirable pH-dependent degradability. After intravenous injection, MoOx@F127 nanosheets were degraded at physiological pH and were rapidly excreted from normal organs, while they were effectively accumulated and retained long-term in the more acidic tumor tissue. This simultaneously ensured effective tumor ablation after NIR irradiation and avoided long-term retention and toxicity in vivo. Compared to chemotherapy or photothermal therapy alone, in vitro and in vivo tumor ablation studies have shown a notably improved synergistic effect of the combination therapy. Our study presents a multifunctional nanosystem with a desirable degradability for chemo-photothermal combination cancer therapy that has great potential in biomedical applications.

Sulfated polysaccharide of Sepiella Maindroni ink inhibits the migration, invasion and matrix metalloproteinase-2 expression through suppressing EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells.

Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni, showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38-specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis.

Tunicamycin potentiates paclitaxel-induced apoptosis through inhibition of PI3K/AKT and MAPK pathways in breast cancer.

PURPOSE: Paclitaxel has been reported to upregulate both AKT and MAPK signaling pathways and thereby compromises its antitumor efficacy. However, tunicamycin has the ability to downregulate AKT and MAPK pathways. The aim of the study is to investigate the antitumor activity of the combination treatment of paclitaxel with tunicamycin and the mechanisms involving the changes of antitumor efficacy. METHODS: Sulforhodamine B (SRB) assay was used to examine the cell viability upon treatment of breast cancer cells with paclitaxel, tunicamycin and the combination of both. Cell cycle distributions and apoptosis were detected by flow cytometry. Western blotting and immunofluorescence staining were used to analyze the effect of drugs on tubulin polymerization. The antitumor growth of combined treatment was measured in nude mice bearing MDA-MB-231 xenograft. Western blotting was performed to explore the alteration of AKT and MAPK pathways in vitro and in vivo. RESULTS: SRB assay and nude mice experiment showed that tunicamycin synergistically enhanced paclitaxel-induced inhibition of cell proliferation and tumor growth. Tunicamycin had no clear effect on paclitaxel-induced cell cycle arrest, demonstrating that cell cycle distribution was not involved in the enhanced antitumor activity. Both annexin V-FITC/propidium iodide assay and TUNEL assay indicated that the combination of tunicamycin with paclitaxel resulted in significant increased cell apoptosis as compared with individual treatment in vitro and in vivo. Tunicamycin decreased paclitaxel-induced microtubulin polymerization, suggesting that enhanced antitumor effect of paclitaxel was not dependent of microtubulin polymerization. Western blotting analysis confirmed that tunicamycin decreased paclitaxel-induced upregulation of survival signal pathways such as AKT and MAPK. CONCLUSION: These results revealed that tunicamycin synergistically enhanced the antitumor effects of paclitaxel through potentiating apoptosis via inhibiting paclitaxel-induced elevation of AKT and MAPK pathways. This study raised the possibility that the combination of paclitaxel with tunicamycin may be a promising approach for improving the clinical activity of paclitaxel.

Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo.

Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF-7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab.

Inertial-Range Reconnection in Magnetohydrodynamic Turbulence and in the Solar Wind.

In situ spacecraft data on the solar wind show events identified as magnetic reconnection with wide outflows and extended "X lines," 10(3)-10(4) times ion scales. To understand the role of turbulence at these scales, we make a case study of an inertial-range reconnection event in a magnetohydrodynamic simulation. We observe stochastic wandering of field lines in space, breakdown of standard magnetic flux freezing due to Richardson dispersion, and a broadened reconnection zone containing many current sheets. The coarse-grain magnetic geometry is like large-scale reconnection in the solar wind, however, with a hyperbolic flux tube or apparent X line extending over integral length scales.

Anti-tumor activity and the mechanism of SIP-S: A sulfated polysaccharide with anti-metastatic effect.

Our previous studies demonstrated that SIP-S had anti-metastatic activity and inhibited the growth of metastatic foci. Here we report the anti-tumor and immunoregulatory potential of SIP-S. SIP-S could significantly inhibit tumor growth in S180-bearing mice, and the inhibition rates was 43.7% at 30 mg/kg d. Besides, SIP-S could improve the thymus and spleen indices of S180-bearing mice and the mice treated with CTX. The combination of SIP-S (15 mg/kg d) with CTX (12.5 mg/kg d) showed higher anti-tumor potency than CTX (25 mg/kg d) alone. These results indicated that SIP-S had immunoenhancing and anticancer activity, and the immunoenhancing activity might be one mechanism for its anti-tumor activity. Flow cytometry results showed that SIP-S could induce tumor cells apoptosis. Western blot analysis indicated that SIP-S could upregulate the expression of pro-apoptotic proteins, caspase-3, -8, -9 and Bax, and downregulate the expression of anti-apoptotic protein PARP-1 in tumor cells in a dose-dependent manner. In summary, SIP-S has anti-tumor activity, which may be associated with its immunostimulating and pro-apoptotic activity.

An arabinogalactan from flowers of Panax notoginseng inhibits angiogenesis by BMP2/Smad/Id1 signaling.

Angiogenesis plays an essential role in tumor development. Blocking angiogenesis in tumor has become a promising tactic in limiting cancer progression. Here, an arabinogalactan polysaccharide, RN1 was isolated from flowers of Panax notoginseng. Its structure was determined to possess a backbone of 1,6-linked Galp branched at C3 by side 1,3-linked Galp, with branches attached at position O-3 of it. The branches mainly contained 1,5-linked, 1,3,5-linked, terminal Arabinose and terminal Galactose. RN1 could inhibit microvessel formation in the BxPC-3 pancreatic cancer cell xenograft tumor in nude mice. The antiangiogenesis assay showed that RN1 could reduce the migratory activity of endothelial cells and their ability of tube formation on matrigel, but no effect on endothelial cells growth. Further studies revealed that RN1 could inhibit BMP2/Smad1/5/8/Id1 signaling. All those data indicated the RN1 had an antiangiogenic effect via BMP2 signaling and could be a potential novel inhibitor of angiogenesis.

Antitumor effects of a novel histone deacetylase inhibitor NK-HDAC-1 on breast cancer.

Histone deacetylases (HDACs) are overexpressed in various types of primary human cancer and have become attractive targets for cancer therapy. We designed and synthesized a series of new class of HDAC inhibitors (HDACi). Among these, S-(E)-3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide (NK-HDAC-1) showed potent antitumor activity. In the present study, we examined the antitumor effects of NK-HDAC-1 on breast cancer in vitro and in vivo. The inhibitory effects of NK-HDAC-1 on HDAC enzyme activity and cell growth were more potent compared to suberoylanilide hydroxamic acid (SAHA). NK-HDAC-1 caused G1 cell cycle arrest at concentrations below 0.2 µM and G2/M arrest at concentrations above 0.4 µM through p21 upregulation and cyclin D1 downregulation. NK-HADC-1 induced hyperacetylation of histone H3 and H4 around the promoter region of p21. NK-HDAC-1 promoted apoptosis in MDA-MB-231 breast cancer cells by activating both the intrinsic and the extrinsic pathway NK-HDAC-1 at doses of 3, 10 and 30 mg/kg reduced the tumor volume in MDA-MB-231 xenografts by 25.9, 48.8 and 63.6%, respectively. The results suggested that NK-HDAC-1 may be a promising therapeutic candidate in treating human breast cancer.

Anti-metastatic and anti-angiogenic activities of sulfated polysaccharide of Sepiella maindroni ink.

A previous study demonstrated that SIP-SII, a sulfated Sepiella maindroni ink polysaccharide, suppressed the invasion and migration of cancer cells via the inhibition of the proteolytic activity of matrix metalloproteinase-2 (MMP-2). Therefore, this study investigated the anti-metastatic effect of SIP-SII in vivo. SIP-SII (15 and 30 mg/kg d) markedly decreased B16F10 pulmonary metastasis in mice models by 85.9% and 88.0%, respectively. Immunohistochemistry showed that SIP-SII decreased the expression of the intercellular adhesion molecule 1 (ICAM-1) and basic fibroblast growth factor (bFGF) in lung metastasis nodules. In addition, SIP-SII inhibited neovascularization in chick chorioallantoic membrane assay at 0.08-2 mg/mL. In the in vitro experiments, SIP-SII (0.8-500 µg/mL) significantly decreased the protein and mRNA expression of ICAM-1 and bFGF in SKOV3 and EA.hy926 cells, respectively. These results suggested that SIP-SII might suppress melanoma metastasis via the inhibition of the tumor adhesion mediated by ICAM-1 and the angiogenesis mediated by bFGF, as well as resulting in depression of the invasion and migration of carcinoma cells.