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)

The involvement of CXCR4 and CCR5 coreceptors in apoptosis induced by the HIV envelope (Env) proteins has not been well defined. We found that simian human immunodeficiency virus (SHIV) virus-like particles (VLPs) containing HIV Env proteins preferentially induce apoptosis of cells corresponding to their coreceptor usage in a CD4+ T cell line. We also demonstrated that induction of apoptosis by SHIV VLPs is correlated with coreceptor usage in a non-T cell line. We examined the effects of SHIV VLPs containing Env proteins derived from either a T-cell-tropic HIV (BH10) strain or a dual-tropic HIV (89.6) strain on induction of apoptosis in recombinant CD4+ human osteosarcoma (HOS) cells expressing either CXCR4 (HOS-CD4.CXCR4) or CCR5 coreceptors (HOS-CD4.CCR5). HOS-CD4.CXCR4 or HOS-CD4.CCR5 cells were activated with concanavalin A and cocultured with VLPs. By TUNEL (TdT-mediated dUTP-X nick end labeling) fluorescence staining and flow cytometry assays, SHIV BH10 VLPs were found to preferentially induce apoptosis in HOS-CD4.CXCR4 cells but not in HOS-CD4 or HOS-CD4.CCR5 cells. On the other hand, SHIV 89.6 VLPs induced an elevated level of apoptosis in both HOS-CD4.CXCR4 and HOS-CD4.CCR5 cells in a dose-dependent fashion. These data demonstrate that T-cell-tropic BH10 Env preferentially utilizes CXCR4, but not CCR5, for induction of apoptosis, whereas dual-tropic 89.6 Env induces apoptosis in both CXCR4- and CCR5-containing cell lines.
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PMID:HIV envelope proteins differentially utilize CXCR4 and CCR5 coreceptors for induction of apoptosis. 1141 13

Simian virus 40 small t antigen (st) is required for optimal transformation and replication properties of the virus. We find that in certain cell types, such as the human osteosarcoma cell line U2OS, st is capable of inducing apoptosis, as evidenced by a fragmented nuclear morphology and positive terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining of transfected cells. The cell death can be p53 independent, since it also occurs in p53-deficient H1299 cells. Genetic analysis indicates that two specific mutants affect apoptosis induction. One of these (C103S) has been frequently used as a PP2A binding mutant. The second mutant (TR4) lacks the final four amino acids of st, which have been reported to be unimportant for PP2A binding in vitro. However, TR4 unexpectedly fails to bind PP2A in vivo. Furthermore, a long-term colony assay reveals a potent colony inhibition upon st expression, and the behavior of st mutants in this assay reflects the relative frequency of nuclear fragmentation observed in transfections using the same mutants. Notably, either Bcl-2 coexpression or broad caspase inhibitor treatment could restore normal nuclear morphology. Finally, fluorescence-activated cell sorting analysis suggests a correlation between the ability of st to modulate cell cycle progression and apoptosis. Taken together, these observations underscore that st does not always promote proliferation but may, depending on conditions and cell type, effect a cell death response.
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PMID:Induction of p53-independent apoptosis by simian virus 40 small t antigen. 1153 78

As previously reported, the association of bone loss with an increase in bone marrow adipose volume may be related to the inhibition of human osteoblastic cell proliferation in the presence of human adipocytes. In the osteoblastic supernatant, fatty acid composition varied after coculture with mature adipocytes, with a marked increase in the proportion of docosahexaenoic acid (22:6 n-3; DHA) (+90 +/- 8%). This suggests that polyunsaturated fatty acids (PUFA) may contribute to the inhibitory effect of adipocytes on osteoblastic cell proliferation. The purpose of the present study was to evaluate the effects of two PUFA, DHA and arachidonic acid (20:4 n-6; AA), on the proliferation of primary human osteoblastic (hOB) cells and human osteosarcoma cell line, MG-63. The effects of cholesterol and oleic acid, a monounsaturated FA (18:1 n-9; OA), both being present in adipocyte lipidic vacuoles, were also investigated. At between 10 and 50 micromol/L, DHA and AA induced a significant dose-dependent decrease in hOB cell proliferation (p < 0.0001 and p < 0.006 for DHA and AA, respectively) when compared with control hOB cells exposed to the vehicle (bovine serum albumin). This inhibition reached -50% with 50 micromol/L of DHA or 20 micromol/L of AA. This effect was not related to cell apoptosis, as shown by terminal deoxynucleotidyltransferase-mediated dUTP-fluorescein nick end labeling (TUNEL) and Hoechst dye staining. In contrast, OA and cholesterol had no effect on hOB cell proliferation, even at a high concentration (200 micromol/L). Similar results were observed with regard to MG-63 cell proliferation. In addition, flow cytometric analysis showed that the number of hOB cells in the S phase of the cycle was twofold lower when treated with 50 micromol/L of DHA or AA. In vitro results indicate that mature adipocytes may contribute to age-related bone loss through the release of polyunsaturated fatty acids, which impair osteoblastic proliferation.
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PMID:Role of polyunsaturated fatty acids in the inhibitory effect of human adipocytes on osteoblastic proliferation. 1211 Apr 43

The pattern of inhibition of cell proliferation and cytotoxicity in vitro by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (Naph-DNB) was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the trypan blue (TB) dye exclusion assays in nine murine and human cell lines of different histologic origin. In our culture conditions Naph-DNB showed a good inhibiting activity against all cell lines tested, with IC(50)s varying within a narrow micromolar range of concentrations (2.0 +/- 0.2-14.3 +/- 2.3 microM). In particular, murine P388 (leukemia), human Jurkat (leukemia), A2780, PA-1 (ovarian carcinoma) and Saos-2 (osteosarcoma) cells showed the highest sensitivity to the inhibiting potential of Naph-DNB, while human A549 (non small cell lung cancer, NSCLC), MDA-MB-231 (breast cancer), HGC-27 (gastric cancer) and HCT-8 (colon carcinoma) were the least sensitive cell lines. Moreover, the analysis of cytotoxicity of Naph-DNB evaluated by the TB test showed that this compound was able to kill cells with IC(50)s ranging from 1.7 to 39.2 microM. The study of the induction of apoptosis was carried out by 4'-6-diamidine-2'-phenylindole (DAPI) staining of segmented nuclei, western blot of p53 protein and TdT-mediated dUTP-biotin nick end labeling (TUNEL) method, while the interaction with DNA was evaluated through the analysis of interstrand cross-link (ISCL) formation. Our data show that in all cell lines tested Naph-DNB was able to form ISCLs, to upregulate p53 oncosuppressor-protein and to induce apoptosis. Moreover, TUNEL analysis also suggested that Naph-DNB, similarly to other anticancer drugs, was able to block cells in the G (0)/ G (1) phase of the cell cycle. In conclusion our data suggest that Naph-DNB may be an effective novel lead molecule for the design of new anticancer compounds.
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PMID:Preliminary evaluation in vitro of the inhibition of cell proliferation, cytotoxicity and induction of apoptosis by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene. 1529 6

Cyclooxygenase-2 (COX-2) inhibitors exert antitumor activity via COX-2-dependent and independent pathways. We wished to evaluate the antitumor activity of meloxicam, a preferential COX-2 inhibitor, in osteosarcoma, the most common primary malignant bone tumor, and determine whether its antitumor effect is COX-2-dependent. COX-2 expression in the osteosarcoma cell lines MG-63, HOS and U2-OS was determined by real-time RT-PCR and western blotting. Subsequently, the inhibitory effects of meloxicam on osteosarcoma cell growth and invasiveness were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and matrigel invasion assays, respectively. Apoptotic activity was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining and semi-quantification of Bax and Bcl-2 expression by real time RT-PCR and western blotting. Prostaglandin-E(2) (PGE(2)) production in the presence and absence of meloxicam was analyzed by enzyme immunoassay, and to determine whether the effects of meloxicam are COX-2-dependent or independent, PGE(2) was added to see if it reversed the effects of meloxicam. In addition, the effects of meloxicam on tumor growth and metastasis were evaluated in an in vivo mouse model using grafted LM-8 mouse osteosarcoma cells, together with immunohistochemical analysis for vascular endothelial growth factor in lung metastatic lesion. Meloxicam inhibited PGE(2) production, proliferation and invasiveness especially in MG-63 cells, which express relatively high levels of COX-2. Only high concentrations of meloxicam caused apoptosis and upregulated Bax mRNA and protein in MG-63 cell culture. In contrast, meloxicam did not induce apoptosis in HOS and U2-OS cells, expressing relatively low levels of COX-2. Exogenous PGE(2) reduced the effects of meloxicam on cell viability and invasiveness, but not its effect on Bax mRNA. In vivo, high doses of meloxicam suppressed LM-8 tumor growth and lung metastasis. Meloxicam, may have both COX-2-dependent and independent inhibitory actions on osteosarcoma. Its effects are more prominent in osteosarcoma cells that have relatively high levels of COX-2.
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PMID:Meloxicam inhibits osteosarcoma growth, invasiveness and metastasis by COX-2-dependent and independent routes. 1621 34

Cyclooxygenase-2 (COX-2) inhibitors have been shown to exert inhibitory effects on many types of malignant tumors and several groups have suggested that COX-2 inhibitors enhance the cytotoxic effects of other anti-cancer agents. We previously reported that meloxicam has an anti-tumorigenic effect on COX-2-expressing osteosarcoma cells. In the current study, we evaluated the synergy between meloxicam and cisplatin (CDDP), doxorubicin (DXR) and 4-hydroperoxy ifosfamide (4OOH-IFM), using the human osteosarcoma cell line, MG-63. Cytotoxicity was determined using 3-(4,5'-dimethylthiazol-2-yl)-2,5'-diphenyltetrazolium bromide (MTT) assays, and isobolographic analysis was used to evaluate any synergy. Apoptotic activity was determined by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and by evaluating Bax and Bcl-2 expression levels using real-time RT-PCR and western blotting analysis. Cell cycling was evaluated by flow cytometry. The cytotoxic effects of CDDP and DXR were enhanced synergistically in the presence of meloxicam and were partially due to an increase in apoptosis. By contrast, meloxicam enhanced neither the cytotoxic nor the apoptotic activity of 4OOH-IFM. Combining meloxicam with DXR significantly up-regulated Bax expression, whereas it down-regulated Bcl-2 expression in combination with CDDP. Furthermore, the number of cells in the G2/M phase was significantly increased in DXR-treated samples by the addition of meloxicam, but not in CDDP-treated or 4OOH-IFM-treated samples. These results suggest a potential clinical application of meloxicam in combination with cytotoxic drugs in patients with COX-2-positive osteosarcoma.
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PMID:Synergistic effects of meloxicam and conventional cytotoxic drugs in human MG-63 osteosarcoma cells. 1739 21