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)

XIAP-associated factor 1 (Xaf1) binds XIAP and re-localizes it to the nucleus, thus inhibiting XIAP activity and enhancing apoptosis [1]. Xaf1 expression is reduced or absent in tumor samples and cell lines suggesting it may function as a tumor suppressor [2-5]. To further study Xaf1 function we generated Xaf1 inducible cells in the osteosarcoma cell line Saos-2. Despite Xaf1 inducing apoptosis that is dramatically enhanced by TNFalpha we find no evidence for an interaction between Xaf1 and XIAP. Furthermore, Xaf1 expression sensitized XIAP-/- fibroblasts to TNFalpha, demonstrating the existence of a novel mechanism of Xaf1 induced apoptosis distinct from antagonizing XIAP. Xaf1 expression promotes cytochrome c release that cannot be blocked by inhibition of caspase activity. This implicates a role for the mitochondrial apoptotic pathway, consistent with the ability of Bcl2 to block Xaf1 induced apoptosis. The data indicate that in Saos2 cells Xaf1 activates the mitochondrial apoptotic pathway to facilitate cytochrome c release, thus amplifying apoptotic signals from death receptors.
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PMID:Xaf1 can cooperate with TNFalpha in the induction of apoptosis, independently of interaction with XIAP. 1643 62

Redistribution of cytochrome c and Smac/DIABLO from mitochondria occurs during apoptosis, although the relative timing of their release is not well characterized. Double immunocytochemistry was utilized here to study quantitatively the patterns of release of cytochrome c and Smac/DIABLO from mitochondria in single cells. Human osteosarcoma cells and murine embryonic cortical neurons were analyzed during apoptosis induced by staurosporine. In osteosarcoma cells treated with staurosporine for 24 h, a substantial proportion of cells (36%) released cytochrome c from the mitochondria before Smac/DIABLO. In contrast, these proteins were released mostly concordantly in neurons; only a minority of cells (< or = 15%) released cytochrome c without Smac/DIABLO (or vice versa) from mitochondria. Patterns of release in either cell type were unaltered by addition of the caspase inhibitor, zVAD-fmk. The double immunocytochemistry procedure facilitated clear definition of the temporal release of cytochrome c and Smac/DIABLO from mitochondria in intact apoptotic cells, enabling us to demonstrate for the first time that their mutual redistribution during apoptosis varies between different cell types.
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PMID:Relative timing of redistribution of cytochrome c and Smac/DIABLO from mitochondria during apoptosis assessed by double immunocytochemistry on mammalian cells. 1662 37

Previous studies have shown that oridonin, a diterpenoid isolated from Rabdosia rubescens, was able to inhibit proliferation and induce apoptosis in several cell types. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effect and mechanisms of action of oridonin in human osteosarcoma cells. Our results demonstrated that oridonin induced concentration- and time-dependent suppression of proliferation and activation of apoptosis in U2OS, MG63 and SaOS-2 osteosarcoma cell lines. Oridonin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). These events were all inhibited by z-VAD-fmk, a universal inhibitor of caspases. Oridonin treatment dephosphorylated constitutively active AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). In addition, oridonin decreased the phosphorylation of ERK and increased the phosphorylation of p38 MAPK and JNK. Furthermore, oridonin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in osteosarcoma cells. All together, our results suggested that oridonin is able to inactivate Akt and ERK and activate p38 MAPK and JNK signalling pathways in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
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PMID:Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells. 1721 75

Grifolin, a natural biologically active substance isolated from the edible bodies of the mushroom Albatrellus confluens, has been shown to inhibit proliferation and induce apoptosis in several cancer cell lines. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effects and the mechanisms of grifolin on human osteosarcoma cells. Our results demonstrated that grifolin induced concentration- and time-dependent suppression of proliferation and induction of apoptosis in U2OS and MG63 osteosarcoma cell lines. Grifolin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, z-VAD-fmk, a universal inhibitor of caspases, prevented caspase-3 activation and PARP cleavage and inhibted grifolin-induced cell growth inhibition. Furthermore, grifolin treatment resulted in a reduction in level of phosphorylated AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). Knockdown of GSK3 with siRNA inhibited the apoptotic effects of grifolin. On the other hand, grifolin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in both osteosarcoma cells. Taken together, our results suggested that grifolin is able to suppress the phosphorylation of Akt and its substrates FOXO transcription factor and GSK3 in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
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PMID:Grifolin induces apoptosis via inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells. 1733 16

Flavonoids have antioxidant and antitumor promoting effects. Rhus verniciflua Stokes (RVS) is a flavonoid-rich herbal medicine that has long been used in Korea as both a food additive and antitumor agent. It was previous reported that a purified flavonoid fraction prepared from RVS, herein named RCMF (the RVS chloroform-methanol fraction), inhibited the proliferation and induced apoptosis in human osteosarcoma (HOS) cells. This study examined the mechanisms involved in the RCMF-mediated apoptosis in HOS cells. RCMF was shown to be capable of inducing apoptosis in HOS cells by inducing p53 in the cells resulting in the decrease in Bcl-2 level, activation of Bax, and cytoplasmic release of cytochrome c, which led to the translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) into the nucleus. However, the RCMF-induced apoptosis was suppressed by transfecting the cells with antisense p53 oligonucleotides but not by treating them with a MAPK or caspase inhibitor. This suppression occurred through the regulation of Bcl-2 members as well as by preventing the nuclear translocation of the mitochondrial apoptogenic factors. Overall, it appears that p53-mediated mitochondrial stress and the nuclear translocation of AIF and EndoG are mainly required for the apoptosis induced by RCMF.
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PMID:Caspase-independent death of human osteosarcoma cells by flavonoids is driven by p53-mediated mitochondrial stress and nuclear translocation of AIF and endonuclease G. 1735 95

Glioblastomas are high-risk primary brain tumors that are generally unresponsive or only weakly responsive to the currently available antineoplastic agents. Thus novel therapeutic strategies and agents are urgently needed to treat these incurable cancers. Oleanolic acid and ursolic acid are naturally occurring triterpenoids that have been used in traditional Asian medicine as anti-inflammatory and anti-cancer agents. Recently, synthetic oleanolic acid triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives have been shown to exhibit potent antitumor activity against diverse types of tumor cell lines, including leukemia, multiple myeloma, osteosarcoma, breast, lung, and pancreatic cancer cell lines; however, the anticancer activity of these agents for brain tumors has not been reported. In the present study, we investigated the apoptosis-inducing activity of CDDOs in glioblastoma (U87MG, U251MG) and neuroblastoma (SK-N-MC) cell lines. Cell growth/viability (MTS) and cytotoxicity (LDH release) assays demonstrated that glioblastoma cell lines are least sensitive to CDDO, but are highly sensitive to CDDO-Me and CDDO-Im at concentrations of 2.5-10 muM. CDDO-Im and CDDO-Me were equipotenent in their growth inhibitory activity. The primary mode of tumor cell destruction was apoptosis as demonstrated by significant increase in the number of hypo-diploid (sub-G0) cells and annexin V-FITC binding. Induction of apoptosis was associated with the activation of procaspases-3, -8, and -9, mitochondrial depolarization and the release of cytochrome c from mitochondria. Furthermore, CDDO-Me inhibited the levels of anti-apoptotic and prosurvival p-Akt, NF-kappaB (p65) and Notch1 signaling molecules. These studies provide rationale for clinical evaluation of these novel agents for the management of lethal brain neoplasms.
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PMID:Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. 1736 29

Chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, may be responsible for serious adverse effects like encephalopathy in ifosfamide chemotherapy. In this study, we demonstrate that chloroacetaldehyde, but not ifosfamide, induces cell death in human osteosarcoma Saos-2 cells and we investigated the mechanism by which this occurs. Chloroacetaldehyde above 30 micromol/l induced significant cell death in a time-dependent manner. Thiol compounds such as N-acetyl cysteine, glutathione and dithiothreitol protected the cells against chloroacetaldehyde-induced cell death, although other nonthiol compounds and the antioxidative enzymes superoxide dismutase and catalase did not, suggesting that reactive oxygen species might not mediate cell death. In cells exposed to chloroacetaldehyde, levels of both total thiols and glutathione were significantly reduced. Chloroacetaldehyde also collapsed the mitochondrial membrane potential of these cells, induced the release of cytochrome c from mitochondria to the cytosol and significantly reduced cellular ATP levels during the course of death. The mitochondrial potential collapse was also prevented by thiol compounds. Flow cytometric analyses by means of annexin-V and propidium iodide double staining and immunofluorescence staining of active caspase-3 revealed that cells subjected to a lethal dose of chloroacetaldehyde displayed features characteristic of necrosis and that caspase-3 was not activated in response to chloroacetaldehyde. Taken together, these findings suggest that Saos-2 cells exposed to chloroacetaldehyde die by necrosis resulting from a decrease in intracellular thiols, disruption of the mitochondrial membrane potential and the depletion of cellular ATP.
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PMID:Necrotic pathway in human osteosarcoma Saos-2 cell death induced by chloroacetaldehyde. 1741 23

Oncostatin M (OSM), a cytokine of the interleukin-6 family, induces growth arrest and differentiation of osteoblastic cells into glial-like/osteocytic cells. Here, we asked whether OSM regulates apoptosis of normal or transformed (osteosarcoma) osteoblasts. We show that OSM sensitizes cells to apoptosis induced by various death inducers such as staurosporine, ultraviolet or tumor necrosis factor-alpha. Apoptosis is mediated by the mitochondrial pathway, with release of cytochrome c from the mitochondria to the cytosol and activation of caspases-9 and -3. DNA micro-arrays revealed that OSM modulates the expression of Bax, Bad, Bnip3, Bcl-2 and Mcl-1. Pharmacological inhibitors, dominant-negative signal transducer and activator of transcriptions (STATs), stable RNA interference and knockout cells indicated that the transcription factors p53 and STAT5, which are activated by OSM, are implicated in the sensitization to apoptosis, being responsible for Bax induction and Bcl-2 reduction, respectively. These results indicate that, in addition to growth arrest and induced differentiation, OSM also sensitizes normal and transformed osteoblasts to apoptosis by a mechanism implicating (i) activation and nuclear translocation of STAT5 and p53 and (ii) an increased Bax/Bcl-2 ratio. Therefore, association of OSM with kinase inhibitors such as Sts represents new therapeutic opportunities for wild-type p53 osteosarcoma.
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PMID:Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53. 1747 Dec 33

Multimodal therapies play important roles in the treatment of osteosarcoma (OS) and Ewing's family of tumors (EFTs), two most frequent malignant bone tumors. Although the clinical outcome of primary OS and EFTs is greatly improved, the relapsed cases often are associated with multidrug resistance of the tumors and the prognosis of these patients is still poor. Flavopiridol, a pan cyclin-dependent kinase (CDK) inhibitor is a novel antitumor agent that can induce cell cycle arrest and apoptosis in many cancer cells. However, there have been no studies about the effects of flavopiridol on drug-resistant OS and EFTs. Here, we demonstrated that flavopiridol induced the cleavage of poly-ADP-ribose polymerase (PARP) in a time and dose dependent manner in adriamycin-resistant OS and EFTs cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP(1)) as effectively as in their parental cells. Our data also showed that flavopiridol caused the release of mitochondrial cytochrome c and the activation of caspase-9, caspase-8 and caspase-3, with an increase ratio of the proapoptotic protein level (Bax) to the antiapoptotic protein level (Bcl-2 and Bcl-X(L)), while apoptosis was inhibited by pan caspase inhibitor (Z-VAD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK), not by caspase-8 inhibitor (Z-IETD-FMK). The treatment with flavopiridol further inhibited the tumor growth in mouse models of the drug-resistant OS and EFTs. These results suggest that flavopiridol might be promising in clinical therapy for the relapsed OS and EFTs.
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PMID:Cyclin-dependent kinase inhibitor, flavopiridol, induces apoptosis and inhibits tumor growth in drug-resistant osteosarcoma and Ewing's family tumor cells. 1752 Jun 76

The prognostic significance of bax, cytochrome c, and caspase-8 in patients with primary osteosarcoma is unknown. We examined the immunohistochemical expression of these genes in 35 surgically treated patients with primary osteosarcoma. Clinicopathological and survival data were correlated with the staining result. Eighteen tissue specimens from non-malignant osseous lesions were used as controls. Bax, cytochrome c, and caspase-8 positive staining was observed in 29 (82.9%), 16 (45.7%), and 0 (0%) patients, respectively, but did not stain any of the 18 benign osseous lesions used as controls. None of the genes studied predicted overall or disease-free survival. Patients, however, bearing bax(+)/cytochrome c(+) or bax(+)/cytochrome c(+ +) tumors had a decreased 4-year disease-free survival rate compared to the rest of the group (p = 0.0489 and p = 0.0208, respectively), identifying two groups of patients where more intensive adjuvant treatment could possibly be applied to prevent high postoperative recurrence rates.
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PMID:Prognostic value of bax, cytochrome C, and caspase-8 protein expression in primary osteosarcoma. 1815 79


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