Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TRAP-1 is a mitochondrial heat shock protein (HSP), recently identified in Saos-2 osteosarcoma cells adapted to mild oxidative stress induced by diethylmaleate (DEM). TRAP-1 mRNA expression is increased in DEM-adapted cells as well as in tumor cells resistant to 5-fluorouracil and to platin derivatives. Since a strong decrease of TRAP-1 protein levels, upon cisplatin treatment, is observed only in controls but not in the DEM-adapted counterpart, a possible role for this protein in the development of resistant phenotypes could be hypothesized. To characterize the protective role of TRAP-1 against oxidative stress and apoptosis, stable transfectants were generated and characterized for their response to different stress types. These stable clones expressing constitutively high TRAP-1 levels: (i) are more resistant to H2O2-induced DNA damage and to apoptosis by cisplatin; (ii) contain higher reduced glutathione (GSH) levels than control cells; and (iii) do not release the apoptosis-inducing factor into the nucleus upon cisplatin treatment. Furthermore, high TRAP-1 levels interfere with caspase 3 activation. These results confirm the anti-apoptotic role of TRAP-1, and suggest that increased expression of this mitochondrial HSP in DEM-adapted and chemoresistant cells could be part of a pro-survival signaling pathway aimed to evade toxic effects of oxidants and anticancer drugs.
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PMID:Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. 1785 63

Sulforaphane (SFN), a naturally occurring isothiocyanate, is an attractive agent due to its potent anticancer effects. SFN suppresses the proliferation of various cancer cells in vitro and in vivo. In this study, we report that SFN inhibited the proliferation of cultured murine osteosarcoma LM8 cells. Twenty micromolar SFN completely inhibited the growth of LM8 cells and caused G2/M-phase arrest. SFN induced the expression of p21(WAF1/CIP1) protein causing the cell cycle arrest in a dose-dependent manner. SFN induced apoptosis which was characterized by the appearance of cells with sub-G1 DNA content and the cleavage and activation of caspase-3. We showed that SFN induced the growth arrest and up-regulated the expression of p21(WAF1/CIP1) protein in a p53-independent manner in human osteosarcoma MG63 cells. We found that intraperitoneal administration of SFN (1 or 2 mg, 5 times/week) significantly inhibited the growth of LM8 xenografts to <30% of the controls in a preclinical animal model without causing any toxicity. In osteosarcoma cells, our findings provide in vivo evidence for the efficacy of SFN against the advanced growth of tumor. We showed that SFN induces cell cycle arrest and apoptosis in osteosarcoma cells and inhibits tumor xenograft growth. Furthermore, SFN is a potent inducer of p21(WAF1/CIP1) in osteosarcoma cells. These results raise the possibility that SFN may be a promising candidate for molecular-targeting chemotherapy against osteosarcoma.
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PMID:Sulforaphane induces cell cycle arrest and apoptosis in murine osteosarcoma cells in vitro and inhibits tumor growth in vivo. 1791 83

Curcumin (diferuloylmethane), one of the main components of the Indian spice turmeric, is known to possess potent anti-inflammatory and anti-oxidant properties. In addition, curcumin has also been shown to have in vitro and in vivo efficacy against a variety of malignancies. In the current study we examined the cytotoxic effect of curcumin on seven osteosarcoma (OS) cell lines with varying degrees of in vivo metastatic potential. Curcumin inhibited the growth of all OS cell lines tested with half-maximal inhibitory concentration values ranging from 14.4 to 24.6 microM. Growth inhibition was associated with a dose dependent increase in the number of apoptotic cells and accumulation of cells in the G(2)/M phase of the cell cycle. Curcumin treatment also resulted in cleavage of caspase-3 and poly adenosine diphosphate-ribose polymerase. Moreover, curcumin treatment was associated with an increase in cellular levels of the apoptotic B-cell leukemia/lymphoma 2 (Bcl-2)-associated X protein and a decrease in cellular content of the anti-apoptotic protein Bcl-2. In addition, curcumin treatment also inhibited the migration of OS cell lines. These data indicate that the potent cytotoxic activity of curcumin on OS cell lines is mediated by induction of apoptotic processes. Thus, curcumin has potential to be a novel OS chemotherapeutic agent.
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PMID:Cytotoxic effects of curcumin on osteosarcoma cell lines. 1807 34

Aluminium (Al) has been investigated as a neurotoxic substance. Al ranks among the potential environmental risk factors for Alzheimer's disease (AD). Epidemiological studies tested the relationship between Al in drinking water and AD, showing a significant correlation between elevated levels of monomeric Al in water and AD, although data to date remain inconclusive with respect to total Al. The aim of this study was to test whether or not Al exacerbates cellular toxicity mediated by the amyloid beta (Abeta) peptide. We evaluated the role of Al in modulating programmed cell death (apoptosis) in human cell cultures. We used the osteosarcoma cell line monolayer (SaOs-2) to demonstrate that treatment of SaOs-2 cultures with the Abeta peptide mid-fragment (25 to 35) at nano M, followed by co-incubation with physiological concentrations of aluminium chloride, which release monomeric Al in solution, led to marked expression of caspase 3, but not caspase 9, key markers of the apoptotic process. The same experimental conditions were shown to blunt significantly the proliferative response of normal human peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA) stimulation. Our observations support the hypothesis that Al significantly impairs certain cellular immune responses, and confirm that Al-mediated cell toxicity may play an important role in AD.
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PMID:Aluminium blunts the proliferative response and increases apoptosis of cultured human cells: putative relationship to Alzheimer's disease. 1808 47

The growth inhibitory effect of a mixture of t,t conjugated linoleic acid isomers (t,t CLA) was investigated in the human osteosarcoma cell MG-63, with references to c9,t11 and t10,c12 CLA isomers. The t,t CLA effectively induced a cytotoxic effect in a time-dependent (0 to 6 d) and concentration-dependent (0 to 40 microM) manner, as compared to the reference and control treatments. The apoptosis and cell cycle related parameters were measured on the cells treated with 40 microM t,t CLA for 4 d. Flow cytometric analysis revealed that the t,t CLA treatment effectively increased the proportion of apoptotic cells with a low DNA content (sub G0/G1) and a marked loss of cells from the G0/G1 phase of the cell cycle, relative to other treatments. The occurrence of the characteristic morphological changes and DNA fragmentation confirmed the apoptosis. The level of Bax protein was increased, whereas the Bcl-2 expression was reduced. In addition, cytochrome c was released from the mitochondria into the cytosol, and the activation of caspase-3 led to the cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, the composition of linoleic and arachidonic acids in membrane was decreased by increase in t,t CLA. These findings suggest that t,t CLA incorporation in membrane activates a mitochondria-mediated apoptosis pathway that can enhance the antiproliferative effect of t,t CLA in the osteosarcoma cells.
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PMID:Growth inhibition of osteosarcoma cell MG-63 by a mixture of trans,trans conjugated linoleic acid isomers: possible mechanistic actions. 1821 79

2-Methoxyestradiol (2-ME) has been found to possess antitumor activity in vivo and in vitro. It has been suggested that 2-ME induces apoptosis resulting in G2/M arrest of tumor cells. In this study, the effect of 2-ME was evaluated in rat osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines. 2-ME was used at final concentrations of 100 nM to 2 microM. The effect of 2-ME on cell growth was measured by the MTS assay. Induction of apoptosis and activation of caspase-3 were investigated along with apoptosis-related gene expression. The data showed that 2-ME significantly inhibited cell growth, inducing apoptosis. The activity of caspase-3 was increased at 20 h and 40 h in both cell lines. 2-ME induced p16 expression, which was possibly involved in the apoptotic process. These results suggested that the 2-ME-induced apoptosis of rat osteosarcoma and rat MFH cells was accompanied by caspase-3 activation through p16 induction.
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PMID:Growth inhibition and induction of apoptosis by 2-methoxyestradiol in rat osteosarcoma and malignant fibrous histiocytoma cell lines. 1839 77

Detachment of adherent cells from extracellular matrix results in apoptosis, a process termed "anoikis". Resistance to anoikis is implicated in the progression of many malignancies by facilitating the migration and eventual colonization of distant sites. Human kidney epithelial cells 293T, human osteoblast cells hFOB 1.19 and human osteosarcoma cells Saos-2 significantly underwent anoikis when adherence was prevented. But human osteosarcoma MG-63 cells were distinctly anoikis resistant when detached. They formed large aggregates and showed little apoptosis compared to the other cells. When MG-63 cells were in suspension, caspase-8, physically associated with death receptor was activated by cell-matrix detachment, whereas. Caspase-3 and caspase-9 were not activated. Translational level of Bcl-2 significantly increased in a time-dependent manner, but the level of beta-catenin and PI3K did not. Caspase-8 participates in an anoikis-inducing process in MG-63 cells at an early time, and overexpression of Bcl-2 blocks activation of caspase-8 making MG-63 cells anoikis resistant.
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PMID:Bcl-2 and caspase-8 related anoikis resistance in human osteosarcoma MG-63 cells. 1867 69

1. It has been shown that the antidepressant desipramine is able to induce increases in [Ca(2+)](i) and cell death in MG63 human osteosacroma cells, but whether apoptosis is involved is unclear. In the present study, the effect of desipramine on apoptosis and the underlying mechanisms were explored. It was demonstrated that desipramine induced cell death in a concentration- and time-dependent manner. 2. Cells treated with 100-800 mmol/L desipramine showed typical apoptotic features, including an increase in sub-diploid nuclei and activation of caspase 3, indicating that these cells underwent apoptosis. Immunoblotting revealed that 100 mmol/L desipramine activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Although pretreatment of cells with 20 mmol/L PD98059 (an ERK inhibitor) or 20 mmol/L SP600125 (an inhibitor of JNK) did not inhibit cell death, the addition of 20 mmol/L SB203580 (a p38 MAPK inhibitor) partially rescued cells from apoptosis. Desipramine-induced caspase 3 activation required p38 MAPK activation. 3. Pretreatment of cells with BAPTA/AM (20 mmol/L) to prevent desipramine-induced increases in [Ca(2+)](i) did not protect cells from death. 4. The results of the present study suggest that, in MG63 human osteosarcoma cells, desipramine causes Ca(2+)-independent apoptosis by inducing p38 MAPK-associated activation of caspase 3.
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PMID:Desipramine-induced Ca-independent apoptosis in Mg63 human osteosarcoma cells: dependence on P38 mitogen-activated protein kinase-regulated activation of caspase 3. 1898 28

Papillomavirus binding factor (PBF) was first identified as a transcription factor regulating the promoter activity of human papillomavirus. We previously demonstrated that PBF is an osteosarcoma-associated antigen and 92% of osteosarcoma tissues express PBF in the nucleus. Moreover, PBF-positive osteosarcoma has a significantly poorer prognosis than that with negative expression of PBF. In the present study, we assessed the biological role of PBF in cell survival. Overexpression of PBF induced cell death-mediated lactate dehydrase (LDH) release from 293EBNA cells. Cleaved poly(ADP-ribose) polymerase and active caspase-3 were also detected. However, PBF-induced apoptosis did not affect caspase-9 activity. Next, to identify the apoptosis regulator of PBF, we screened a cDNA library constructed from mRNA of the osteosarcoma cell line OS2000 using a yeast two-hybrid system and isolated Scythe/BAT3. Scythe/BAT3 mRNA was detected in 56% of osteosarcoma tissues and ubiquitously in various normal tissues. Although Scythe/BAT3 was localized to the cytoplasm in normal tissue, it was localized to the nucleus in osteosarcoma tissue. PBF and Scythe/BAT3 also colocalized to the cytoplasm in 293T cells and the nucleus in OS2000. Furthermore, overexpression of Scythe/BAT3 suppressed cell death events that resulted from overexpression of PBF in OS2000, but not in 293EBNA cells. Thus, our results support the ideas that: (i) PBF could induce apoptotic cell death via a caspase-9-independent pathway; (ii) the apoptosis regulator Scythe/BAT3 is a PBF-associated molecule acting as a nucleus-cytoplasm shuttling protein; and (iii) colocalization of PBF and Scythe/BAT3 in the nucleus might be an important factor for survival of osteosarcoma cells.
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PMID:Scythe/BAT3 regulates apoptotic cell death induced by papillomavirus binding factor in human osteosarcoma. 1901 58

The type 1 insulin-like growth factor receptor (IGF-1R) is essential for tumorigenicity, tumor proliferation, and protection from apoptosis. IGF-1R overexpression has been found in many human cancers including osteosarcoma. To explore its possibility as a therapeutic target for the treatment of osteosarcoma, lentivirus-mediated siRNA was employed to downregulate endogenous IGF-1R expression to study the function of IGF-1R in tumorigenesis and radioresistance of osteosarcoma cells. The IGF-1R expression was persistently and markedly reduced by lentivirus-mediated RNAi. Downregulation of IGF-1R expression in osteosarcoma cells significantly suppressed their growth rates in vitro and reduced the potential of tumorigenicity in vivo. Moreover, the specific downregulation arrested cells in G(0)/G(1) phase of cell cycle and also induced apoptosis which correlated with the activation of Caspase-3. Furthermore, we also observed that suppression of IGF-1R could reduce the invasiveness of osteosarcoma cells and enhance their radiosensitivity. Our study suggested that lentivirus-mediated RNAi silencing targeting IGF-1R could induce potent antitumor activity and radiosensitizing activity in human osteosarcomas.
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PMID:Lentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits growth, reduces invasion, and enhances radiosensitivity in human osteosarcoma cells. 1922 91


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