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Background: Structural elements in pectin that inhibit galectin-3, a ␤-galactoside-binding protein associated with cancer progression, are poorly defined. Results: Both backbone and side chains of pectin RG-I-4 were important for its anti-galectin-3 activity. Conclusion: High activity of RG-I-4 was due to cooperation between short ␤1,4-galactan side chains. Significance: The results are valuable for producing highly active pectin-based galectin-3 inhibitors.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. However, acquired resistance of cancer cells to TRAIL is a roadblock. Agents that can either potentiate the effect of TRAIL or overcome resistance to TRAIL are urgently needed. This article reports that ginsenoside compound K (CK) potentiates TRAIL-induced apoptosis in HCT116 colon cancer cells and sensitizes TRAIL-resistant colon cancer HT-29 cells to TRAIL. On a cellular mechanistic level, CK downregulated cell survival proteins including Mcl-1, Bcl-2, surviving, X-linked inhibitor of apoptosis protein and Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein, upregulated cell pro-apoptotic proteins including Bax, tBid and cytochrome c, and induced the cell surface expression of TRAIL death receptor DR5. Reduction of DR5 levels by siRNAs significantly decreases CK- and TRAIL-mediated apoptosis. Importantly, our results indicate, for the first time, that DR5 upregulation is mediated by autophagy, as blockade of CK-induced autophagy by 3-MA, LY294002 or Atg7 siRNAs substantially decreases DR5 upregulation and reduces the synergistic effect. Furthermore, CK-stimulated autophagy is mediated by the reactive oxygen species–c-Jun NH2-terminal kinase pathway. Moreover, we found that p53 and the C/EBP homologous (CHOP) protein is also required for DR5 upregulation but not related with autophagy. Our findings contribute significantly to the understanding of the mechanism accounted for the synergistic anticancer activity of CK and TRAIL, and showed a novel mechanism related with DR5 upregulation.

A neutral polysaccharide fraction (WGPN) prepared from Panax ginseng C.A. Meyer by hot water extraction and DEAE-cellulose chromatography was tested for its anticancer activity alone and in combination with 5-fluorouracil (5-FU) in Sarcoma-180 (S180) tumor-bearing mice by intragastric administration. WGPN alone inhibited S180 tumor growth in a bell-shaped dose-response curve, and the combination with 5-FU showed a synergistic effect. Studies of various immunological activities in S180-bearing mice revealed that WGPN stimulated the proliferation of lymphocytes, increased natural killer cell cytotoxicity, enhanced the phagocytosis and nitric oxide production by macrophages, and increased the level of tumor necrosis factor-alpha in serum. In combination with 5-FU, WGPN mitigated damage to the immune system caused by 5-FU in S180-bearing mice. These results suggest that WGPN might be a potential adjuvant for chemotherapeutic drugs.

Accumulating evidence indicates that the formation of tumor cell platelet emboli complexes in the blood stream is a very important step during metastases and that the anti-metastasis effects of heparin are partially due to a blockade of P-selectin on platelets. In this study, heparin and chemically modified heparins were tested as inhibitors of three human colon carcinoma cell lines (COLO320, LS174T, and CW-2) binding to P-selectin, adhering to CHO cells expressing a transfected human P-selectin cDNA, and adhering to surface-anchored platelets expressing P-selectin under static and flow conditions. The aim was to screen for heparin derivatives with high anti-adhesion activity but negligible anticoagulant activity. In this study, four modified heparins with high anti-adhesion activity were identified including RO-heparin, CR-heparin, 2/3ODS-heparin, and N/2/3DS-heparin. NMR analysis proved the reliability of structure of the four modified heparins. Our findings suggested that the 6-O-sulfate group of glucosamine units in heparin is critical for the inhibition of P-selectin-mediated tumor cell adhesion. Heparan sulfate-like proteoglycans on these tumor cell surfaces are implicated in adhesion of the tumor cells to P-selectin. Some chemically modified heparins with low anticoagulant activities, such as 2/3ODS-heparin, may have potential value as therapeutic agents that block P-selectin-mediated cell adhesion and prevent tumor metastasis.Hematogenous metastasis is a highly regulated and dynamic process in which the cancerous cells separate from the primary tumor, migrate across blood vessel walls into the bloodstream, and disperse throughout the body to generate new colonies. Several lines of experiments have demonstrated that platelets can facilitate hematogenous dissemination of tumor cells (1). In this process, platelets act mainly through emboli complexes formed by the interaction of tumor cells and platelets. The formation of tumor cell-platelet emboli complexes in the blood stream not only provides a protective shield that masks them from the cytotoxic activity of natural killer cells, but also favors tumor cell adhesion to vascular endothelial cells (2-4).The interaction between tumor cells and platelets may involve several kinds of adhesion molecules. Selectins are a family of intercellular adhesion molecules that mediate the initial adhesion of leukocytes to the endothelia of blood vessels during inflammation (5-9). The family includes E-, P-, and L-selectin, and all three selectins can bind to sialylated, fucosylated, or, in some cases, sulfated glycans on glycoproteins, glycolipids, or proteoglycans (10). The tetrasaccharides [Neu5Ac␣2,3Gal␤1,4-(Fuc␣1,3)GlcNAc] (sLe x ) 1 and [Neu5Ac␣2,3Gal␤1,3(Fuc␣1,4)-GlcNAc] (sLe a ) have been identified as the minimal ligands for all three types of selectins. Recently, accumulating evidence indicates that P-selectin plays a crucial role during hematogenous metastasis, and P-selectin has been shown to bind to several human cancers and human cancer-derived cell lines, s...

Long non-coding RNAs (lncRNAs) have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a small number of lncRNAs were screened and characterized. Here, we identified 15 lncRNAs, which are associated with fatty liver disease. Among them, APOA4-AS is shown to be a concordant regulator of Apolipoprotein A-IV (APOA4) expression. APOA4-AS has a similar expression pattern with APOA4 gene. The expressions of APOA4-AS and APOA4 are both abnormally elevated in the liver of ob/ob mice and patients with fatty liver disease. Knockdown of APOA4-AS reduces APOA4 expression both in vitro and in vivo and leads to decreased levels of plasma triglyceride and total cholesterol in ob/ob mice. Mechanistically, APOA4-AS directly interacts with mRNA stabilizing protein HuR and stabilizes APOA4 mRNA. Deletion of HuR dramatically reduces both APOA4-AS and APOA4 transcripts. This study uncovers an anti-sense lncRNA (APOA4-AS), which is co-expressed with APOA4, and concordantly and specifically regulates APOA4 expression both in vitro and in vivo with the involvement of HuR.

Ginseng polysaccharide has anticancer activity. However, the structure-activity relationship and the activity mechanism are still unclear. Therefore, it is necessary to study the anticancer activity of structurally different ginseng polysaccharide fractions and their potential mechanisms. Ginseng polysaccharide fractions and their temperature-modified products were assayed for their effects on HT-29 cell proliferation by MTT assay, on cell cycle progression by flow cytometry, and on caspase-3 activation by western blot analysis. The HG-rich ginseng pectin inhibited cell proliferation and induced cell cycle arrest in the G2/M phase. The temperature-modified HG-rich pectin had dramatically increased antiproliferative effect and induced apoptosis accompanied by the activation of caspase-3. Starch-like glucan and arabinogalactan of ginseng exhibited no antiproliferative effects. Even after temperature modification, their inhibitory effects either remained unchanged or increased slightly. The HG-rich pectin exerts its antiproliferative effect via cell cycle arrest and the temperature modification markedly increased the antiproliferative effect.