Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current treatment of osteosarcoma is associated with poor prognosis, especially due to the increased risk of developing other cancers with chemotherapy. Therefore, new, safe and effective treatment strategies are needed. We investigated the effect of a unique mixture of nutrients containing lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate (EGCG) on human osteosarcoma cell lines U-2OS, MNNG-HOS, and Ewing's sarcoma SK-ES-1 by measuring: cell proliferation, expression of matrix metalloproteinase-2 (MMP-2), MMP-9, and invasive and angiogenesis potential. Cell proliferation was evaluated by MTT assay, matrix metalloproteinases (MMP) expression by gelatinase zymography, VEGF expression by ELISA, and invasion through Matrigel. Cells were also treated with phorbol 12-myristate 13-acetate (PMA) to study enhanced MMP and VEGF expression. The invasion of osteosarcoma U-2OS and MNNG-HOS cells through Matrigel was significantly reduced in a dose-dependent fashion, with 100% inhibition of invasion of U-2OS cells at 100 microg/ml, and MNNG cells at 50 microg/ml concentration of the synergistically acting nutrient mixture. Ewing's sarcoma SK-ES-1 cells were not invasive. Nutrient synergy (NS) exhibited a dose response antiproliferative effect on osteosarcoma U-2OS cells, reaching 67% at 1000 microg/ml of NS; no significant suppression of cell proliferation was seen with MNNG or Ewing's sarcoma cells. Zymography showed dose-dependent inhibition of MMP secretion by all three cell lines in the presence of NS. VEGF secretion by U-2OS cells was completely blocked at 500 microg/ml of NS. Our results suggest NS is an excellent candidate for therapeutic use in the treatment of osteosarcoma, by inhibiting cancer cell invasion, and secretion of MMPs and VEGF, all critical parameters for cancer control and prevention.
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PMID:Antitumor effect of nutrient synergy on human osteosarcoma cells U-2OS, MNNG-HOS and Ewing's sarcoma SK-ES.1. 1564 7

Prostacyclin, one of the cyclooxygenase metabolites, causes various biological effects, including vasodilation and antithrombogenicity, and is also involved in several pathophysiological effects, such as inflammatory pain and bladder disorders. The prostacyclin receptor (IP receptor) agonists iloprost, cicaprost, and carbacyclin have been useful for clarifying the role of the IP receptor signaling, since the endogenous ligand, prostacyclin, is very unstable. On the other hand, only a few IP receptor antagonists have been reported to date. Here, we characterized the biological activities of 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid (compound A) in various in vitro systems. Compound A inhibited the accumulation of the second messenger cyclic AMP in the UMR-108 rat osteosarcoma cell line and primary cultured rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner up to 10 microM, without affecting other eicosanoid receptors. Functionally, the IP receptor plays an important role in DRG neuron sensitization, which is measured by release of the neurotransmitter substance P. Although the effects of iloprost or Lys-bradykinin, an inflammatory peptide, alone on substance P release were limited, stimulation of the neurons with both these ligands induced substantial amounts of substance P release. This synergistic effect was suppressed by compound A. Collectively, these results suggest that compound A is a highly selective IP receptor antagonist that inhibits iloprost-induced sensitization of sensory neurons. Furthermore, these findings suggest that IP receptor antagonist administration may be effective for abnormal neural activities of unmyelinated sensory afferents. Compound A should prove useful for further investigations of the IP receptor in various biological processes.
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PMID:A prostacyclin receptor antagonist inhibits the sensitized release of substance P from rat sensory neurons. 1610 42

Degradation of extracellular matrix (ECM) is a hallmark of tumor invasion, metastasis and angiogenesis. Based on the Rath multitargeted approach to cancer using natural substances to control ECM stability and enhancing its strength, we developed a novel formulation (NM) of lysine, proline, ascorbic acid and green tea extract that has shown significant anti-cancer activity against a number of cancer cell lines. The aim of the present study was to determine whether NM exhibits anti-angiogenic and anti-metastatic effects using in vitro and in vivo experimental models. Angiogenesis was measured using a chorioallantoic membrane (CAM) assay in chick embryos and bFGF-induced vessel growth in C57BL/6J female mice. To determine the in vivo effect of NM on the tumor xenograft growth, male nude mice were inoculated with 3 x 10(6) MNNG-HOS cells. Control mice were fed a mouse chow diet, while the test group was fed a mouse chow diet supplemented with 0.5% NM for 4 weeks. In vitro studies on cell proliferation (MTT assay), MMP expression (zymography) and Matrigel invasion were conducted on human osteosarcoma U2OS, maintained in McCoy medium, supplemented with 10% FBS, penicillin and streptomycin in 24-well tissue culture plates and tested with NM at 0, 10, 50, 100, 500, and 1000 microg/ml in triplicate at each dose. NM at 250 microg/ml caused a significant (p<0.05) reduction in bFGF-induced angiogenesis in CAM. NM inhibited tumor growth of osteosarcoma MNNG-HOS cell xenografts in nude mice by 53%; furthermore, tumors in NM-treated mice were less vascular and expressed lower levels of VEGF and MMP-9 immunohistochemically than tumors in the control group. In addition, NM exhibited a dose-dependent inhibition of osteosarcoma U2OS cell proliferation (up to 60% at 1000 microg/ml), MMP-2 and -9 expression (with virtual total inhibition at 500 microg/ml NM), and invasion through Matrigel (with total inhibition at 100 microg/ml NM). Moreover, NM decreased U2OS cell expression of VEGF, angiopoietin-2, bFGF, PDGF and TGFbeta-1. These results together with our earlier findings suggest that NM is a relatively non-toxic formulation, which inhibits growth, invasion, metastasis, and angiogenesis of tumor cells.
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PMID:Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angiogenesis. 1614 36

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling. MMPs, VEGF, Ki-67 (proliferative protein), and constituents of ECM play a critical role in angiogenesis and underlie neoplastic invasion and metastasis. This prompted us to investigate the effect of a diet containing lysine, proline, arginine, ascorbic acid, and green tea extract (NM) on the growth of tumors induced by implanting human osteosarcoma MNNG in athymic nude mice and the expression of MMPs, VEGF, Ki-67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). We also investigated the effect of the supplemented diet on serum ascorbic acid, total protein content, alkaline phosphatase activity, and liver enzymes. Athymic male nude mice (n = 12) were inoculated with 3 x 10(6) osteosarcoma cells MNNG-HOS and randomly divided into group A (fed a regular diet) and group B (fed a regular diet supplemented with 0.5% NM). Four weeks later, the mice were sacrificed. Results showed that NM inhibited the growth and reduced the size of tumors in nude mice. Histological evaluation revealed increased mitotic index, MMP-9, and VEGF secretion in the control group tissues. Results demonstrate that the nutrient mixture of lysine, proline, arginine, ascorbic acid, and green tea extract tested strongly suppressed the growth of tumors without adverse effects in nude mice, suggesting potential as an anticancer agent.
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PMID:Effect of ascorbic acid, lysine, proline, and green tea extract on human osteosarcoma cell line MNNG-HOS xenografts in nude mice: evaluation of tumor growth and immunohistochemistry. 1701 99

The human osteosarcoma-derived cell line, SAOS-2, exhibits many of the phenotypic characteristics of osteoblasts including the deposition of types I and V collagens in an extracellular matrix. Lesser amounts of collagen XI chains were also detected. The cell layer collagen contains hydroxylysyl pyridinoline cross-links but without the accompanying lysyl pyridinoline typical of human bone collagen. This indicates that the lysine residues at the two helical cross-linking loci are fully hydroxylated. The isoform of lysyl hydroxylase, LH1, known to be required for full hydroxylation at these sites, was shown to be highly expressed by SAOS-2 cells. Our findings provide insight on the mechanism of post-translational overmodification of lysine residues in collagen made by osteosarcoma tumors, and may be relevant for understanding a similar overmodification observed in osteoporotic bone.
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PMID:The post-translational phenotype of collagen synthesized by SAOS-2 osteosarcoma cells. 1732 Apr 98

Food-derived bioactive peptides are reported to express a variety of functions in vivo. We studied the in vitro effect of three bioactive tripeptides, isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-lysine-proline (LKP), on osteoblast proliferation and gene expression. We used UMR-106 osteosarcoma cells, human marrow-derived mesenchymal stem cells (hMSC) and osteoblasts differentiated from hMSC. Treatment with 50 mum-IPP increased UMR-106 cell and hMSC proliferation. The gene expression of hMSC-differentiated osteoblasts was analysed by the microarray method. Microarray analysis revealed that IPP up-regulated 270 genes and down-regulated 100 genes. VPP and LKP, by contrast, had a very modest influence on osteoblast gene expression. Real-time PCR confirmed that IPP up-regulated PTHrP, BMP-5 and CREB-5 and down-regulated VDR and caspase-8. IPP possesses potential to increase osteoblast proliferation, differentiation and signalling. Agents that increase the number and function of osteoblasts could improve bone mass and structure, and decrease fracture risk.
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PMID:Effects of bioactive peptides isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-lysine-proline (LKP) on gene expression of osteoblasts differentiated from human mesenchymal stem cells. 1746 96

Enhanced supplementation with certain naturally occurring nutrients and vitamins has been associated with a reduction in occurrence and progression of human cancer. The exact mechanisms of this action are still under investigation. Extracellular matrix (ECM) plays a key role in the development of cancer. Therefore, we studied whether nutrients could exert anticancer effects through alteration of ECM biological properties. Confluent cultures of normal human dermal fibroblasts were allowed to produce and deposit ECM during a 7 d incubation period in the presence of tested compounds. Subsequently, fibroblasts were removed and the growth rates of freshly placed cultures of human osteosarcoma cells (lines U2-OS, MMNG, or SK.ES1) on pre-formed ECM were assayed in plain cell growth medium. In addition, ECM was deposited by fibroblasts on the upper surface of a porous plastic membrane and the subsequent migration of osteosarcoma cells to the other side was assayed in non-supplemented medium. The results demonstrated that the ECM produced by normal fibroblasts treated with a mixture of ascorbic acid, lysine, proline, arginine, cysteine, and green tea polyphenols significantly reduced the growth rate and invasive activity of osteosarcoma cells in contrast to the non-supplemented control. The changes in ECM properties were accompanied by significant changes in ECM protein and glycosaminoglycan composition as assayed immunochemically. We conclude that anticancer effects of nutrients involve beneficial changes in ECM biological properties. The role of ECM components in ECM-dependent regulation of tumor cell activities is discussed.
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PMID:Naturally produced extracellular matrix inhibits growth rate and invasiveness of human osteosarcoma cancer cells. 1784 46

The expression of the chondromodulin-I (ChM-I) gene, a cartilage-specific gene, is regulated by the binding of Sp3 to the core promoter region, which is inhibited by the methylation of CpG in the target genome in the osteogenic lineage, osteosarcoma (OS) cells. The histone tails associated with the hypermethylated promoter region of the ChM-I gene were deacetylated by histone deacetylase 2 (HDAC2) in three ChM-I-negative OS cell lines. Treatment with an HDAC inhibitor induced the binding of Sp3 in one cell line, which became ChM-I-positive. This process was associated with acetylation instead of the dimethylation of histone H3 at lysine 9 (H3-K9) and, surprisingly, the demethylation of the core promoter region. The demethylation was transient, and gradually replaced by methylation after a rapid recovery of histone deacetylaion. These results represent an example of the plasticity of differentiation being regulated by the cell-specific plasticity of epigenetic regulation.
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PMID:Cell-specific epigenetic regulation of ChM-I gene expression: crosstalk between DNA methylation and histone acetylation. 1798 Jan 51

RIZ1 isoform, but not RIZ2, is commonly silenced in many types of tumors. In osteosarcoma cells, RIZ1 protein is very abundant. The silencing of YY1 protein, a recent target gene in osteosarcoma cells, reduced the expression of RIZ1 protein. Here we show that RIZ1 overexpression is a transcriptional event documented by Western blot, RT-PCR, and promoter assays. YY1 protein binds and cooperates to positive regulation of the RIZ1 promoter and its presence reduced the dimethyl lysine 9 histone 3 by chromatin immunoprecipitation assays. These results indicate that overexpression of YY1 in osteosarcoma cells plays a key role in positive regulation of RIZ1. The coexpression of RIZ1/YY1 proteins suggests a tandem regulatory mechanism in human osteosarcoma cells and tissues.
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PMID:Silencing of YY1 downregulates RIZ1 promoter in human osteosarcoma. 1848 13

In 1990, an 18-month-old Micronesian girl was initially diagnosed with a right adrenocortical carcinoma. More than a decade later (2003), she was diagnosed with metastatic osteosarcoma with the primary in her right proximal fibula. Given this child's remarkable history of malignancy, she underwent testing for a genetic mutation that is associated with increased cancer formation. One such cancer syndrome is called Li-Fraumeni syndrome where approximately 70% of patients carry a genetic mutation in the p53 tumor suppressor gene. Patients with LFS are at risk for developing cancers of the breast, soft tissues, brain, bone, adrenal gland, and blood cells. Mutational analysis of our patient did reveal the presence of a germline mutation of the p53 tumor suppressor gene. She was found to have a base pair change (A-->C) at nucleotide 394 resulting in a lysine to glutamine amino acid change at codon 132 (K132Q), which remarkably has never been described in association with either adrenocortical carcinoma or osteosarcoma.
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PMID:Germline p53 mutation in a Micronesian child with adrenocortical carcinoma and subsequent osteosarcoma. 1898 56


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