UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined whether low dose radiation (LDR) exposure (75 mGy) could increase the therapeutic efficacy of cyclophosphamide (CTX) by comparing the effects of tumor suppression, tumor cell apoptosis, cell cycle and proliferation of bone marrow in vivo. Kunming mice implanted with S(180) sarcoma cells were given 75 mGy whole body gamma-ray radiation exposure and CTX (300 mg/kg) by intraperitoneal injection 36 hours after LDR. Proliferation of bone marrow and tumor cells was analyzed by flow cytometry. Cytochrome c leakage from the tumor was measured by Western-blot. We discovered that tumor growth was significantly reduced in the group exposed to CTX add to LDR. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G(1) phase in the groups treated with CTX and CTX + LDR, but cell cycle was more significantly arrested in mice exposed to LDR followed by CTX than in mice exposed only to LDR or CTX chemotherapy. Concentration of bone marrow cells and proliferation index in CTX + LDR mice were higher than those in the untreated mice. LDR or CTX + LDR could induce greater cytochrome c levels and caspase-3 activity in tumors. These results suggest that low dose radiation can enhance the anti-tumor effect of the chemotherapy agent CTX markedly. Furthermore, LDR significantly protects hematopoetic function of the bone marrow, which is of practical significance on adjuvant chemotherapy.
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PMID:Low dose radiation increased the therapeutic efficacy of cyclophosphamide on S(180) sarcoma bearing mice. 1754 41

Despite its alarming appearance, spermatocytic seminoma virtually never metastasizes. We hypothesized that this paradox may at least be partially related to increased apoptosis compared to metastasizing germ cell tumors since high expression of proapoptotic factors correlates with indolent behavior in other tumor systems, notably CD30-positive cutaneous lymphoma, another neoplasm where phenotype and behavior do not match. We therefore compared apoptosis and apoptotic regulators in 17 spermatocytic seminomas (2 with sarcoma) and 18 usual seminomas by light microscopy and using immunostains for caspase-3, p53, bcl-2, bcl-xL, FADD, FAS and survivin. We found significantly greater numbers of apoptotic cells and activated caspase-3-positive cells in spermatocytic seminoma compared to usual seminoma (P<0.01). There was over a 10-fold range in apoptotic cells in usual seminoma but only a 4-fold variation in spermatocytic seminoma. Spermatocytic seminoma had decreased p53 expression compared to usual seminoma, with marked variation in bcl-2 expression and increased FADD. The two sarcomas in spermatocytic seminoma, however, showed decreased apoptosis and caspase-3 reactivity, with upregulation of p53 and bcl-2 and decreased FADD expression. We conclude that apoptosis, caspase-3 and FADD expression are increased in spermatocytic seminoma compared to usual seminoma. Apoptotic parameters are decreased in sarcomatous transformation of spermatocytic seminoma. The increased apoptosis of spermatocytic seminoma, possibly mediated by FAS independent activation of the death receptor pathway, may provide some insight into its excellent prognosis. The variation in apoptosis of usual seminomas merits investigation as a prognostic parameter.
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PMID:Apoptosis in spermatocytic and usual seminomas: a light microscopic and immunohistochemical study. 1764 97

The investigation deals with the role of Fas, FasL, RIP, caspase 3, and PARP taking part in Fas-mediated apoptosis, and contributing to in vitro interaction of hepatoma MH-22a and histiocytic sarcoma J-774 in mice with syngenic splenocytes. Protein expression was identified by means of indirect immunofluorescence. There were two patterns of interaction of tumor cells and splenocytes: apoptosis occurred either in 80% or in an insignificant number of tumor cells. In the latter case, high Fas expression was identified before and when it dropped after the experiment. FasL expression in tumor cells often peaked before the experiment and then it decreased after contact with lymphocytes. That mechanism was reversed in splenocytes: contact with tumor cells boosted expression. RIP, caspase 3 and PARP expression was very low and failed to show until the experiments on both patterns of cells were undertaken. After the experiments, it either remained latent or soared up. In the latter case, simultaneous expression of all proteins took place both in tumor cells and lymphocytes. A second battery of experiments demonstrated maximum rates of apoptosis both of tumor cells and splenocytes. However, the situation was different: Fas expression intensified in both patterns of cells after their interaction which was followed by post-experimental drop in RIP, caspase 3, and PARP expression in tumor cells; hence, the importance of perforin/granzyme-mediated apoptosis which occurred at the early stages of tumor growth in the midst of interaction with immune system cells. That pattern of apoptosis was highly cytotoxic. It is suggested that Fas-mediated apoptosis or any other receptor-sensitive pathway might take place during tumor progression, i.e. at a stage when tumor is most susceptible to change.
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PMID:[Role of proteins in Fas-mediated apoptosis in tumor cells and lymphocytes co-cultured in vitro]. 1766 73

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, divided into two major histological subtypes, embryonal (ERMS) and alveolar (ARMS). To explore the possibility that the proteasome could be a target of therapeutic value in rhabdomyosarcoma, we treated several RMS cell lines with the proteasome inhibitor bortezomib (Velcade or PS-341) at a concentration of 13-26 nM. RMS cells showed high sensitivity to the drug, whereas no toxic effect was observed in primary human myoblasts. In both ERMS and ARMS cells bortezomib promoted apoptosis, activation of caspase 3 and 7 and induced a dose-dependent reduction of anchorage-independent growth. Furthermore, bortezomib induced activation of the stress response, cell cycle arrest and the reduction of NF-kappaB transcriptional activity. Finally, bortezomib decreased tumour growth and impaired cells viability, proliferation and angiogenesis in a xenograft model of RMS. In conclusion, our data indicate that bortezomib could represent a novel drug against RMS tumours.
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PMID:Bortezomib-mediated proteasome inhibition as a potential strategy for the treatment of rhabdomyosarcoma. 1834

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Highly malignant, RMS frequently fails to respond to conventional aggressive multimodal radiation, surgery, and chemotherapy treatment protocols that also cause significant sequelae in the growing child. Other tumors of mesenchymal origin, such as locally aggressive fibromatoses and desmoid tumors, have been successfully treated with a selective estrogen receptor (ER) modulator, tamoxifen. In an effort to identify new targets for RMS therapy, our group investigated the previously uncharacterized ER pathway in RMS cell culture and primary tumors. We detected ER isoform beta (ER beta), but not isoform alpha, RNA, and protein in five RMS cell lines. Immunohistochemical staining of primary RMS tumor sections confirmed high levels of ER beta but not ER alpha protein. RMS cell growth was dramatically inhibited in steroid-free conditions, and this growth inhibition was rescued with 17-beta-estradiol (E2) supplementation. Exposure of RMS cells to 4'OH-tamoxifen (4OHT) decreased cell viability and inhibited colony formation as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony-forming assays. 4OHT also induced apoptotic signaling in RMS cells as detected by cleavage of caspase-3 and poly(ADP)ribose polymerase. This effect increased 3- to 8-fold in steroid-deprived conditions but was rescued by supplementation with E2. Immunofluorescence studies detected a change in the subcellular localization of ER beta in response to 4OHT. Together, these data suggest an active ER beta-mediated signal transduction pathway in RMS. The ability of 4OHT to induce apoptotic signaling and disrupt estradiol-mediated proliferation provides a rationale to explore a role for selective ER modulators in the treatment of RMS.
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PMID:The estrogen receptor pathway in rhabdomyosarcoma: a role for estrogen receptor-beta in proliferation and response to the antiestrogen 4'OH-tamoxifen. 1845 Nov 76

Paclitaxel is a microtubule stabilizing drug that causes dividing cells to arrest and then undergo apoptosis. It also has antiangiogenic activity because it alters cytoskeletal structure, affecting migration and invasion. Paclitaxel is an effective treatment for AIDS-related Kaposi's sarcoma (KS). KS is a tumor in which there is marked proliferation of endothelial cells in addition to the tumor cells, which themselves share many markers with activated (proliferating) endothelial cells.We sought to determine the mechanism by which paclitaxel exerts its anti-KS tumor effects. In vitro, KS cells are very sensitive to paclitaxel, with half-maximal growth inhibition observed at 0.8 nM. Inhibition of migration of KS cells was also observed at nanomolar concentrations of the drug. Paclitaxel induced cell cycle arrest with an accumulation of cells in sub-G1.This was accompanied in vitro by various events typical of apoptosis: phosphorylation of two anti-apoptotic proteins Bcl-2 and Bcl-(xL) , release of cytochrome c into the cytoplasm, cleavage and activation of caspase-3. In vitro results were borne out by studies of KS tumor xenografts in nude mice. Paclitaxel (10 mg/kg) inhibited tumor growth by 75% over 21 days. Histological examination of the tumors revealed a decrease in proliferative index, a decrease in the number of mitotic figures and an increase in apoptotic cells compared to tumors from untreated mice.
Sarcoma 2000
PMID:Paclitaxel Induces Apoptosis in AIDS-Related Kaposi's Sarcoma Cells. 1852 33

The potential biomarkers for the lymphatic metastatic process of mouse hepatocarcinoma were investigated by using two-dimensional difference in-gel electrophoresis (2D DIGE), high-performance liquid chromatography/nano-electrospray ionization tandem mass spectrometry (HPLC/nESI-MS/MS) and GeneChip. 2D DIGE was performed to screen and quantify the differentially expressed proteins between two well-established mouse hepatocarcinoma cell lines, Hca-F with 75% and Hca-P with 25% metastasis rate of lymph node potentials. The protein spots in the gel were visualized by the highly sensitive Deep Purple (GE Healthcare) fluorescent stain. Protein identification was obtained for gel spots by HPLC/nESI-MS/MS analysis with high quality. GeneChip microarray was performed to identify genes differentially expressed at the mRNA level. Seventeen genes including the chloride intracellular channel l, caspase 3, fructose bisphosphatase 2, glutamate dehydrogenase 1, V-crk sarcoma virus CT10 oncogene homolog, N-myc downstream regulated gene1, villin2, gelsolin, enoyl coenzyme A hydratase 1, transketolase, vimentin, annexins A5 and A7, keratin complex2 basic gene7 and gene8, lactamase (bata 2) and Ero1-like protein were found abnormally regulated and expressed concordantly both at the protein and mRNA levels between the two cell lines. More than half of these genes were for the first time revealed to be involved directly in hepatocarcinoma due to the lymphatic metastasis. The interdisciplinary combination of HPLC/nESI-MS/MS with 2D DIGE and GeneChip techniques opens up the possibility for the biomarker discovery of disease with high confidence.
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PMID:High-performance liquid chromatography/nano-electrospray ionization tandem mass spectrometry, two-dimensional difference in-gel electrophoresis and gene microarray identification of lymphatic metastasis-associated biomarkers. 1879 1

IFN regulatory factor 8 (IRF8) has been shown to suppress tumor development at least partly through regulating apoptosis of tumor cells; however, the molecular mechanisms underlying IRF8 regulation of apoptosis are still not fully understood. Here, we showed that disrupting IRF8 function resulted in inhibition of cytochrome c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase cleavage in soft tissue sarcoma (STS) cells. Inhibition of the mitochondrion-dependent apoptosis signaling cascade is apparently due to blockage of caspase-8 and Bid activation. Analysis of signaling events upstream of caspase-8 revealed that disrupting IRF8 function dramatically increases FLIP mRNA stability, resulting in increased IRF8 protein level. Furthermore, primary myeloid cells isolated from IRF8-null mice also exhibited increased FLIP protein level, suggesting that IRF8 might be a general repressor of FLIP. Nuclear IRF8 protein was absent in 92% (55 of 60) of human STS specimens, and 99% (59 of 60) of human STS specimens exhibited FLIP expression, suggesting that the nuclear IRF8 protein level is inversely correlated with FLIP level in vivo. Silencing FLIP expression significantly increased human sarcoma cells to both FasL-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and ectopic expression of IRF8 also significantly increased the sensitivity of these human sarcoma cells to FasL- and TRAIL-induced apoptosis. Taken together, our data suggest that IRF8 mediates FLIP expression level to regulate apoptosis and targeting IRF8 expression is a potentially effective therapeutic strategy to sensitize apoptosis-resistant human STS to apoptosis, thereby possibly overcoming chemoresistance of STS, currently a major obstacle in human STS therapy.
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PMID:IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression. 1915 7

Novel 2-phenyl-4-quinolone compounds have potent cytotoxic effects on different human cancer cell lines. In this study, we examined anticancer activity and mechanisms of 20-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) in human osterogenic sarcoma U-2 OS cells. CHM-1-induced apoptosis was determined by flow cytometric analysis, DAPI staining, Comet assay, and caspase inhibitors. CHM-1-inhibited cell migration and invasion was assessed by a wound healing assay, gelatin zymography, and a Transwell assay. The mechanisms of CHM-1 effects on apoptosis and metastasis signaling pathways were studied using Western blotting and gene expression. CHM-1 induced G2/M arrest and apoptosis at an IC(50) (3 microM) in U-2 OS cells and caspase-3, -8, and -9 were activated. Caspase inhibitors increased cell viability after exposure to CHM-1. CHM-1-induced apoptosis was associated with enhanced ROS generation, DNA damage, decreased DeltaPsi(m) levels, and promotion of mitochondrial cytochrome c release. CHM-1 stimulated mRNA expression of caspase-3, -8, and -9, AIF, and Endo G. In addition, CHM-1 inhibited cell metastasis at a low concentration (<3 microM). CHM-1 inhibited the cell metastasis through the inhibition of MMP-2, -7, and -9. CHM-1 also decreased the levels of MAPK signaling pathways before leading to the inhibition of MMPs. In summary, CHM-1 is a potent inducer of apoptosis, which plays a role in the anticancer activity of CHM-1.
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PMID:Novel quinolone CHM-1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line. 1955 55

Given that arsenic trioxide (As(2)O(3)) has been successfully used as a chemotherapeutic agent for refractory malignant tumors, this study is aimed at investigating the effect of As(2)O(3) on human Adriamycin resistant osteosarcoma cell line Saos-2. The mechanism underlying multi drug resistance (MDR) in osteosarcoma cells and the anti-tumor effect of As(2)O(3) on Adriamycin resistant osteosarcoma cells were analyzed. In our experiment, we first selected Adriamycin resistant osteosarcoma cell line by growing the classic osteosarcoma cell line Saos-2 in the medium with increasing drug concentrations. Then, we compared the IC50s of the osteosarcoma cells treated with different anticancer drugs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Subsequently, we assessed the expression of classic MDR related molecules, Pgp, multidrug resistance-associated protein (MRP) and glutathione (GSH) activity in the wild type and Adriamycin resistant Saos-2 cells. Furthermore, the apoptosis was assessed by concerning DNA fragment and flow cytometry with Annexin-V staining. To elucidate the underlying mechanism of the apoptosis, related proteins Bcl-2, Bcl-xL, Bax, Bak, cleaved Caspase-3 and cleaved Caspase-9 were analyzed by western blotting. The data showed that the resistance to Adriamycin affected the sensitivity of osteosarcoma cell to other chemotherapeutic agents. The IC50s of Saos-2/ADM cells for methotrexate (1.74-fold), Cisplatin (1.43-fold) and As(2)O(3) (1.21-fold) were increased compared with Saos-2 control cells. The expression of Pgp was upregulated comparing with the control cells. No significant difference was detected about the MRP and the glutathione-S-transferase activity and intracellular GSH concentration among different treated osteosarcoma cells. Apoptosis was observed and proved. The western blotting showed that the expression of Bcl-2 and Bcl-xL was downregulated. Meanwhile, the level of Bax, Bak, cleaved Caspase-3 and cleaved Caspase-9 was upregulated after treated with As(2)O(3). The study suggests that Adriamycin resistant osteosarcoma cells have good response to As(2)O(3)-based chemotherapy in vitro, probably via the pathway of inducing apoptosis. And As(2)O(3) might serve as an excellent alternative candidate for adjuvant chemotherapeutic agent on this incurable pediatric sarcoma.
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PMID:Arsenic trioxide inhibits the growth of adriamycin resistant osteosarcoma cells through inducing apoptosis. 1970 92

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