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PubMed2004

Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death.

During camptothecin- and etoposide (VP-16)-induced apoptosis in HL-60 cells, the expression level of cell death receptor-3 (DR3), cell death receptor-4 (DR4), and FAS remained mostly unchanged, whereas the expression of silencers of death domain (SODD) and FLICE inhibitory proteins, inhibitors of the cell death receptor signaling pathways, decreased substantially. By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the cell surface and the appearance of high molecular weight protein complexes primarily involving DR3, and DR3 and DR4 after camptothecin and VP-16 treatment, respectively. Both drugs failed to rapidly promote FAS aggregation in these cells. The high expression level of SODD or of dominant negative forms of FADD (FADD-DN) and DAP3 (DAP3-DN), or of NH2-terminal deletion mutant of TRADD (TRADD-ND) achieved by transient transfection experiments, did not impair the kinetics of apoptosis after camptothecin and VP-16 treatment in HL-60 and U937 cells. Taken together, these observations suggested that camptothecin and VP-16 induced rapid aggregation of DR4 and DR3, but paradoxically, the importance of these events in signaling apoptosis is uncertain, because the kinetics of apoptosis were unaffected, even in the presence of a high expression level of SODD, FADD-DN, TRADD-ND, and DAP3-DN. However, camptothecin or VP-16 treatment in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) substantially accelerated kinetics of apoptosis than treatment with camptothecin, VP-16, or TRAIL alone. In contrast, cotreatment of camptothecin or VP-16 with TWEAK or TL1A did not facilitate apoptosis in HL60 cells. These findings suggest that DR4 aggregation mediated by camptothecin or VP-16 could represent a mean that accelerates TRAIL-induced apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Phorbol myristate acetate inhibits okadaic acid-induced apoptosis and downregulation of X-linked inhibitor of apoptosis in U937 cells.

Okadaic acid is a specific inhibitor of serine/threonine protein phosphatase 1 (PP-1) and 2A (PP-2A). The phosphorylation and dephosphorylation at the serine/threonine residues on proteins play important roles in regulating gene expression, cell cycle progression, and apoptosis. In this study, phosphatase inhibitor okadaic acid induces apoptosis in U937 cells via a mechanism that appears to involve caspase 3 activation, but not modulation of Bcl-2, Bax, and Bcl-X(L) expression levels. Treatment with 20 or 40 nM okadaic acid for 24 h produced DNA fragmentation in U937 cells. This was associated with caspase 3 activation and PLC-gamma1 degradation. Okadaic acid-induced caspase 3 activation and PLC-gamma1 degradation and apoptosis were dose-dependent with a maximal effect at a concentration of 40 nM. Moreover, PMA (phorbol myristate acetate), PKC (protein kinase C) activator, protected U937 cells from okadaic acid-induced apoptosis, abrogated okadaic acid-induced caspase 3 activation, and specifically inhibited downregulation of XIAP (X-linked inhibitor of apoptosis) by okadaic acid. PMA cotreated U937 cells exhibited less cytochrome c release and sustained expression levels of the IAP (inhibitor of apoptosis) proteins during okadaic acid-induced apoptosis. In addition, these findings indicate that PMA inhibits okadaic acid-induced apoptosis by a mechanism that interferes with cytochrome c release and activity of caspase 3 that is involved in the execution of apoptosis.

Apoptosis↗
PubMed2005

Severe cell fragmentation in the endothelial cell apoptosis induced by snake apoptosis toxin VAP1 is an apoptotic characteristic controlled by caspases.

Hemorrhagic snake venom induces apoptosis in vascular endothelial cells (VEC). Vascular apoptosis-inducing protein 1 (VAP1), which is identified as an apoptosis toxin against vascular endothelial cells, induces apoptosis accompanied by severe cell fragmentation compared with that of apoptosis due to other inducers. The mechanism of this morphologic feature is not known. In this report, we examine the roles of the caspases in the apoptosis induced by VAP1. Measurement of the caspase activities shows that activation of caspases occurred in this type of cell death. In the presence of certain caspase inhibitors, the severe cell fragmentation was strongly inhibited. The other hand, cell death induced by VAP1 was not affected by caspase inhibitors. These data suggest that the severe cell fragmentation induced by the snake toxin is a special characteristic of this apoptosis. Apoptosis with severe cell fragmentation may be regarded as a new category of endothelial cell apoptosis.

Animals↗
PubMed2002

Involvement of specific integrins in apoptosis induced by vascular apoptosis-inducing protein 1.

Hemorrhagic snake venom induces apoptosis in vascular endothelial cells (VEC). In previous reports, we described the purification and cDNA cloning from Crotalus atrox of vascular apoptosis-inducing protein 1 (VAP1) that specifically induces apoptosis in VEC. VAP1 belongs to the metalloprotease/disintegrin family. Yet the mechanism of inducing apoptosis by VAP1 is still not known. Since other various metalloproteases and disintegrins in snake venoms are known to influence extracellular matrix and cell adhesion, we investigated here the involvement of these adhesion molecules in VAP1-induced apoptosis. Consequently, VAP1 induced apoptosis without degrading extracellular matrix or inhibiting adhesion of VEC. However, VAP1-induced apoptosis was inhibited by antibodies for integrin alpha3, alpha6, beta1. Additionally, apoptosis was inhibited by antibody for CD9, an integrin associated protein. These results suggest that integrins are involved in VAP1-induced apoptosis by some specific role rather than that of adhesion to extracellular matrix.

Animals↗
PubMed2003

LIGHT sensitizes IFNgamma-mediated apoptosis of MDA-MB-231 breast cancer cells leading to down-regulation of anti-apoptosis Bcl-2 family members.

LIGHT is a new member of the tumor necrosis factor superfamily, which binds to lymphotoxin beta receptor, herpes virus entry mediator, or TR6. This work was carried out to elucidate the molecular mechanism of LIGHT-sensitized, interferon gamma (IFNgamma)-mediated apoptosis of MDA-MB-231 cells. It was revealed that LIGHT treatment resulted in down-regulation of anti-apoptosis Bcl-2 family member: Bcl-2, Bcl-X(L), Bag-1, and Mcl-1; up-regulation of pro-apoptosis Bcl-2 family member: Bak and Ser (112)-phosphor-Bad; down-regulation of pro-apoptosis Bcl-2 member Bax; the other pro-apoptosis member Bid remains unaltered. LIGHT treatment also resulted in activation of caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, DFF45, and PARP. However, caspase activation and caspase activity, especially caspase-3 activity, is not required for LIGHT-induced apoptosis of MDA-MB-231 cells, since caspase-3 inhibitor, benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, and a broad range caspase inhibitor, benzyloxycarbonyl-val-ala-asp-fluoromethylketone failed to block the apoptosis induced by LIGHT and IFNgamma in MDA-MB-231 cells. In summary, LIGHT-sensitized IFNgamma-mediated apoptosis of MDA-MB-231 cells is probably through down-regulation of anti-apoptosis Bcl-2 family members; it could be caspase (especially caspase-3)-independent, even though extensive caspase activation was observed.

Adenocarcinoma↗
PubMed1998

Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by Drosophila proteins HID and GRIM.

Reaper (RPR), HID, and GRIM activate apoptosis in cells programmed to die during Drosophila development. We have previously shown that transient overexpression of RPR in the lepidopteran SF-21 cell line induces apoptosis and that members of the inhibitor of apoptosis (IAP) family of antiapoptotic proteins can inhibit RPR-induced apoptosis and physically interact with RPR through their BIR motifs (D. Vucic, W. J. Kaiser, A. J. Harvey, and L. K. Miller, Proc. Natl. Acad. Sci. USA 94:10183-10188, 1997). In this study, we found that transient overexpression of HID and GRIM also induced apoptosis in the SF-21 cell line. Baculovirus and Drosophila IAPs blocked HID- and GRIM-induced apoptosis and also physically interacted with them through the BIR motifs of the IAPs. The region of sequence similarity shared by RPR, HID, and GRIM, the N-terminal 14 amino acids of each protein, was required for the induction of apoptosis by HID and its binding to IAPs. When stably overexpressed by fusion to an unrelated, nonapoptotic polypeptide, the N-terminal 37 amino acids of HID and GRIM were sufficient to induce apoptosis and confer IAP binding activity. However, GRIM was more complex than HID since the C-terminal 124 amino acids of GRIM retained apoptosis-inducing and IAP binding activity, suggesting the presence of two independent apoptotic motifs within GRIM. Coexpression of IAPs with HID stabilized HID levels and resulted in the accumulation of HID in punctate perinuclear locations which coincided with IAP localization. The physical interaction of IAPs with RPR, HID, and GRIM provides a common molecular mechanism for IAP inhibition of these Drosophila proapoptotic proteins.

Animals↗
PubMed2005

Cleavage of p53-vimentin complex enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of rheumatoid arthritis synovial fibroblasts.

Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to arthritic cartilage degradation. Although RASFs are normally resistant to apoptosis, Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based gene therapy has been successfully used in a mouse model of arthritis. We investigated this further by treating human RASFs with nontoxic doses of the proteasome inhibitor lactacystin. Treatment induced cytosolic accumulation of p53 and enhanced the susceptibility of RASFs to apoptosis mediated by TRAIL-R2 (DR5) but not Fas. A specific role for p53 in TRAIL-R2-mediated apoptosis was indicated by the ability of p53 siRNA to significantly reduce RASF apoptosis and by the reduced apoptosis of RASFs bearing p53 mutations on treatment with anti-DR5 antibody or anti-DR5 antibody plus lactacystin. p53 immunoprecipitation followed by mass spectrometry identified a vimentin-p53 complex, an interaction that was confirmed by reciprocal vimentin-p53 immunoprecipitation and by co-immunofluorescence. Interestingly, human caspase-4 cleaved human vimentin, and blockade of caspase-4 with a chemical inhibitor or with specific siRNA significantly inhibited TRAIL-R2-mediated apoptosis of RASFs. Furthermore, blockade of caspase-4 was paralleled by persistence of a cytosolic pattern of p53 and absence of p53 translocation to the nucleus. Taken together, our findings suggest a unique role for caspase-4 in cleaving vimentin and releasing cytosolic p53 for nuclear translocation, events that may regulate the sensitivity of RASFs to receptor-mediated apoptosis.

Acetylcysteine↗
PubMed2004

Casein kinase I attenuates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by regulating the recruitment of fas-associated death domain and procaspase-8 to the death-inducing signaling complex.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide variety of malignant cell lines, in contrast to normal cells, but with considerable heterogeneity in response. Death receptor-mediated apoptosis may be attenuated by a variety of different mechanisms, including phosphorylation-based signaling pathways. We have demonstrated that casein kinase I can attenuate TRAIL-induced apoptosis in human cell lines derived from colon adenocarcinoma (HT29 and HCT8) and pediatric rhabdomyosarcoma (JR1). Inhibition of casein kinase I (CKI) phosphorylation events in HT29, HCT8, and JR1 cells by CKI-7 dramatically increased apoptosis after exposure to TRAIL, in the absence of apoptosis induced by TRAIL treatment alone. CKI inhibition enhanced the recruitment of Fas-associated death domain and procaspase-8 to the death-inducing signaling complex after TRAIL treatment and enhanced cleavage of procaspase-8 at the death-inducing signaling complex. In HT29 cells studied further, rapid cleavage of caspase-8, caspase-3, Bid, and the caspase substrate poly(ADP-ribose) polymerase occurred when CKI-7 and TRAIL were combined. Overexpression of Bcl-2, Bcl-xL, or mutant DN-Fas-associated death domain protected HT29 cells from TRAIL-induced apoptosis in the presence of the CKI inhibitor. In addition, TRAIL combined with CKI-7 promoted the release of cytochrome c, Smac/DIABLO, HtrA2/Omi, and AIF from the mitochondria and down-regulated the expression of XIAP and c-IAP1. Small hairpin RNAs directed against CKI revealed that the CKIalpha isoform contributed significantly to the inhibition of TRAIL-induced apoptosis. These findings suggest that CKIalpha plays an antiapoptotic role through the generation of phosphorylated sites at the level of the death-inducing signaling complex, thereby conferring resistance to caspase cleavage mediated by TRAIL.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Uveal melanoma expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and susceptibility to TRAIL-induced apoptosis.

PURPOSE: The study had two purposes: to examine the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors on uveal melanoma cells and metastases arising from uveal melanoma and to determine the susceptibility of uveal melanoma cells to TRAIL-induced apoptosis. METHODS: Nine human uveal melanoma cell lines and three cell lines derived from uveal melanoma metastases were examined for TRAIL receptor expression by flow cytometry. In vitro apoptosis assays were performed to determine the relative susceptibility of uveal melanoma cells to TRAIL-induced apoptosis. Annexin V staining was also used to determine the capacity of either cycloheximide or interferon-beta to enhance TRAIL-induced apoptosis. RESULTS: Five of the nine uveal melanoma cell lines expressed TRAIL-R2 on more than 60% of the cells. All three of the cell lines derived from uveal melanoma metastases expressed TRAIL-R2 on more than 50% of the cells. Cycloheximide exerted a profound effect in enhancing TRAIL-induced apoptosis in all but two of the uveal melanoma cell lines and in all three of the metastases cell lines. Interferon-beta produced a similar enhancement of TRAIL-induced apoptosis, even in cell lines that were previously shown to be resistant. CONCLUSIONS: TRAIL is a potentially useful therapeutic modality for the management of uveal melanomas and their metastases. Moreover, pharmacological agents and biological response modifiers that independently display antineoplastic properties can enhance TRAIL-induced apoptosis in resistant uveal melanoma cells.

Annexin A5↗
PubMed2001

Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels.

We have demonstrated that Apo-2 ligand (Apo-2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of human prostate cancer PC-3, DU145, and LNCaP cells in a dose-dependent manner, with PC-3 cells displaying the greatest sensitivity to Apo-2L/TRAIL. Susceptibility of the prostate cancer cell types to Apo-2L/TRAIL-induced apoptosis did not appear to correlate with the levels of the Apo-2L/TRAIL receptors death receptor (DR) 4 (TRAIL receptor 1) or DR5 (TRAIL receptor 2), decoy receptor (DcR) 1 and DcR2, Flame-1, or the inhibitors of apoptosis proteins family of proteins. Apo-2L/TRAIL-induced apoptosis of PC-3 cells was associated with the processing of caspase-8, caspase-10, and the proapoptotic Bid protein, resulting in the cytosolic accumulation of cytochrome c as well as the processing of procaspase-9 and procaspase-3. Cotreatment with the caspase-8 inhibitor z-IETD-fmk or DR4:Fc significantly inhibited Apo-2L/TRAIL-induced apoptosis. Treatment with paclitaxel or taxotere increased DR4 and/or DR5 protein levels (up to 8-fold) without affecting the protein levels of DcR1 and DcR2, Apo-2L/TRAIL, Fas, or Fas ligand. Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide. Importantly, sequential treatment of PC-3, DU145, and LNCaP cells with paclitaxel followed by Apo-2L/TRAIL induced significantly more apoptosis than Apo-2L/TRAIL treatment alone (P < 0.01). This was also associated with greater processing of procaspase-8 and Bid, as well as greater cytosolic accumulation of cytochrome c and the processing of caspase-3. These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells.

Antineoplastic Agents, Phytogenic↗
PubMed2003

[Interleukin-12 enhanced tumor necrosis factor related apoptosis-inducing ligand TRAIL-induced apoptosis in human hepatocellular carcinoma by inhibiting expression of survivin].

OBJECTIVE: To investigate therapeutic potential of TRAIL in hepatocellular carcinoma (HCC) and the mechanism of sTRAIL resistance and to reverse the resistance to sTRAIL-inducing apoptosis. METHODS: The expression profiles of TRAILR were determined 60 HCC samples, in 20 normal liver tissues and 2 HCC cell lines HepG2 and SMMC-7721 by in situ hybridization. Cellular effects of sTRAIL in promoting apoptosis on HCC cell lines HepG2 and SMMC-7721 were analyzed after exposure to recombinant protein and after transfection with a cDNA expression construct. In vivo effects of sTRAIL on tumor growth were investigated using a nude mice HCC model of hepG2. Furthermore, the expression of survivin in HCC was detected, and treatment with antisence oligonucleotide was accepted. Finally, therapeutic effect on HCC by combining sTRAIL and interleukin-12 (IL-12) was detected. RESULTS: Both DR4 and DR5 were present in all HCC tissues as well as normal hepatic tissues. In contrast, 54 HCC tissues did not express DcR1 and 25 did not express DcR2. But both DcR were detectable in all of the normal liver tissues. The expression patterns of DR and DcR in HCC samples were quite different from those in normal tissue. DR5, DR4, and DcR2 expressed in both cell lines, while no DcR1 expression was detected. Recombinant sTRAIL alone was found to have a slight activity as it killed a maximum of 15% of HCC cells within 24 h while killing over 70% of Jurkat cells. In vivo administration of the TRAIL gene couldn't inhibit tumor growth in a nude mice HCC model. Mostly, HCC tissue and both HCC cell lines expressed survivin, whereas normal liver tissue did not express survivin. Treatment with antisence oligonucleotide enhanced sTRAIL-inducing apoptosis. IL-12 significantly augmented sTRAIL-inducing apoptosis and inhibited survivin expression. CONCLUSIONS: HCC cells are insensitive towards TRAIL-mediated apoptosis. Survivin may play a role in resistance to TRAIL-induced apoptosis in HCC, and antisence oligonucleotide could partly reverse the resistance to TRAIL-inducing apoptosis. IL-12 may sensitize HCC cells to TRAIL-induced apoptosis by preventing survivin. Combining gene therapy strategy such as combining gene therapy of TRAIL with IL-12 may be a promising maneuver to HCC.

Animals↗
PubMed1997

bcl-2 and bak may play a pivotal role in sodium butyrate-induced apoptosis in colonic epithelial cells; however overexpression of bcl-2 does not protect against bak-mediated apoptosis.

Butyrate, a short chain fatty acid produced in the colon as a result of fermentation of dietary fibre by symbiotic bacteria, induces apoptosis in colonic tumour cell lines. Three human colonic adenoma cell lines (AA/C1, RG/C2 and BH/C1) and one carcinoma cell line (S/KS/FI) were used to determine the effects of butyrate on the expression of bcl-2, bax and bak to examine the possible role of these proteins in the induction of apoptosis. RG/C2 and BH/C1 cells express p-26-bcl-2 and butyrate treatment decreased p26-bcl-2 levels in association with apoptosis, whereas bax and bak levels remained constant. AA/C1 and S/KS/FI cells have no detectable p26-bcl-2. In S/KS/FI cells, bax or bak levels did not change in response to butyrate. However, in AA/C1 cells, butyrate-induced apoptosis was associated with increased bak levels. Therefore, in AA/C1 cells butyrate-induced apoptosis appears to be mediated through bak. Furthermore, butyrate also induced apoptosis and increased bak levels in AA/C1 cells transfected with a bcl-2 expression vector which expressed high levels of p26-bcl-2. For S/KS/FI cells, two bcl-2 transfectants gave different results. bcl-2 protected against apoptosis in one transfectant in which bak levels were not elevated in response to butyrate, whereas it did not protect in the other transfectant in which bak levels were increased after butyrate treatment. The results suggest that expression of constitutively high levels of p26-bcl-2 only conferred protection against apoptosis when bak levels were not elevated in response to butyrate and that expression of constitutively high levels of p26-bcl-2 does not counter the effects of bak. Different mechanisms appear to be involved in cell death signalling in different tumours since butyrate may induce apoptosis via elevated levels of bak or reduced levels of p26-bcl-2.

Adenoma↗
PubMed1997

Induction of apoptosis and potentiation of TNF- and Fas-mediated apoptosis in U937 cells by the xanthogenate compound D609.

Apoptosis induced by ligation of either the tumor necrosis factor (TNF) p55 receptor or the Fas/APO-1/CD95 receptor has been suggested to require ceramide as a signaling molecule. Ceramide is formed as a result of sphingomyelinase (SMase) activation in the sphingomyelin cycle, and ligation of TNF and Fas receptors has been reported to stimulate SMase activity. We have studied the effects of D609, a xanthogenate compound with antitumoral properties, on TNF- or Fas-induced apoptosis of monocytic U937 cells. First, the effects of D609 on SMase activity were assessed using in vitro assays for neutral and acidic SMase, and the results suggested that D609 caused a modest stimulation of the activity of both SMases in U937 cells. Exposure of U937 cells for 6 h to TNF or anti-Fas mAb induced apoptosis in 40-45% of the cells, as measured by fluorescent staining of nuclear chromatin. Cotreatment with D609 potentiated TNF- as well as Fas-mediated apoptosis up to 70 and 90%, respectively. Furthermore, in incubations with D609 alone, 60% of the cells became apoptotic within 16 h. Since D609 has been reported to inhibit protein kinase C (PKC) activity, the effect of phorbol 12-myristate 13-acetate (PMA) on D609-induced apoptosis was investigated. PMA was found to inhibit D609-induced apoptosis in U937 cells as well as cell death induced by TNF and anti-Fas mAb. Thus, PKC inactivation may play an important role in the regulation of apoptosis in U937 cells. In summary, the present results show that D609 stimulates SMase activity, potentiates TNF- and Fas-induced apoptosis, and induces apoptosis on its own in U937 cells.

Antibodies, Monoclonal↗
PubMed1999

BCL-2 expression in childhood leukemia versus spontaneous apoptosis, drug induced apoptosis, and in vitro drug resistance.

The antileukemic activity of cytotoxic drugs is increasingly thought to be the result of induction of apoptosis. Several proto-oncogenes have been related to the regulation of this process. In this study we evaluated the relation between bcl-2 expression, spontaneous and dexamethasone (DXM) induced apoptosis, and in vitro resistance to DXM, prednisolone (PRD) and cytarabine (ARA) determined using the total cell kill colorimetric methyl-thiazol-tetrazolium salt (MTT) assay, in childhood acute lymphoblastic leukemia (ALL). Drug resistance was expressed as the LC50 value, the drug concentration lethal to 50% of the cells. Fourty-six samples taken at initial diagnosis (iALL) and 31 samples taken at relapse (rALL) were incubated in culture medium, with and without DXM. Bcl-2 expression and apoptosis were measured flowcytometrically, the latter using DNA histogram analysis. Bcl-2 expression was 1.4 fold higher in rALL than in iALL (p = 0.008). Both spontaneous and DXM induced apoptosis increased significantly from 0 to 48 hours (in up to 71%, 81% of the cells respectively). Bcl-2 expression was inversely correlated with the extent of spontaneous apoptosis after 24 hours in iALL (r = -0.40, p = 0.05). Relapsed samples, but not samples obtained at presentation, expressing high levels of bcl-2 displayed increased resistance to drug induced apoptosis (r = -0.63, p = 0.02). In iALL high bcl-2 expression appeared to be related to low LC50 values of ARA. No correlations were found for DXM or PRD. In conclusion, DXM excerts its cytotoxic effect at least partly by means of induction of apoptosis. Bcl-2 inhibits drug induced apoptosis in rALL. However in iALL bcl-2 expression is not associated with increased in vitro drug resistance, nor with increased resistance to drug induced apoptosis.

Apoptosis↗
PubMed2005

T-2 toxin induces apoptosis, and selenium partly blocks, T-2 toxin induced apoptosis in chondrocytes through modulation of the Bax/Bcl-2 ratio.

T-2 toxin is one of the mycotoxins, a group of type A trichothecenes produced by several fungal genera including Fusarium species. In the present study, we have investigated the apoptotic effects of T-2 toxin on chondrocytes and the relationship between T-2 toxin induced chondrocyte apoptosis and its influence on Bcl-2/Bax protein and mRNA expression. We have also examined the inhibitory effects of selenium on chondrocyte apoptosis induced by T-2 toxin. We have combined morphological and biological techniques to establish the relevance of apoptosis in human chondrocyte death induced by T-2 toxin. Treatment with T-2 toxin caused accelerated apoptosis in a concentration dependent manner. The apoptosis induced by T-2 toxin involved an increased Bax/Bcl-2 ratio. Bcl-2 mRNA expression remained unchanged in chondrocyte apoptosis induced by T-2 toxin treatment, while Bax mRNA expression increased following treatment with T-2 toxin. Selenium could partly block the apoptosis of chondrocytes induced by T-2 toxin through decreasing the Bax/Bcl-2 ratio. These results suggest that, under our experimental conditions, apoptosis of chondrocytes can be induced by T-2 toxin (1-20ng/mL) via the Bcl-2 and Bax proteins, and the Bax/Bcl-2 ratio may play a critical role in governing the susceptibility to apoptosis induced by T-2 toxin in human chondrocytes.

Apoptosis↗
PubMed2004

The malignant transformation event as a clonal transformation of apoptosis to anti-apoptosis pathways and of cell cycle dynamics.

Anti-apoptosis, as a more vital aspect of a whole series of progressive steps in carcinogenesis, would appear primarily a phenomenon of variable nonresponsiveness. Programmed cell death, in addition, would appear to affect the individual cell as attributes also of an integral field phenomenon constituted by clones of tumor cells that grow, proliferate and spread. Various modes of development of anti-apoptosis subsequently involving the development of genetic abnormalities would possibly account for transformation as a neoplastic phenomenon. It is in terms of such pathways as telomeric length preservation, of anti-apoptosis as failed activation of apoptosis, and of failed DNA binding events that clonally selected tumor cells would tend to inherently progress to higher grade and stage and to spread systemically. Moreover, clonal and field events would possibly influence in their turn individual cell cyclical activity and programmed cell pathways in neoplastic transformation. Anti-apoptosis would constitute, in fact, a predicted system of pathways that switch from apoptosis as an essential pathway in malignant transformation. Angiogenesis, as a full series of cascade events of a paracrine/autocrine nature, would also participate with anti-apoptosis in a tumor cell cycle transformation that is self-amplifying. Given different modes of how apoptosis would convert to anti-apoptosis in tumorigenesis, perhaps abnormal cell cycle dynamics might also contribute to the evolving nature of such neoplastic transformation.

Apoptosis↗
PubMed2001

Cellular titration of apoptosis with steady state concentrations of H(2)O(2): submicromolar levels of H(2)O(2) induce apoptosis through Fenton chemistry independent of the cellular thiol state.

Apoptosis was studied under conditions that mimic the steady state of H(2)O(2) in vivo. This is at variance with previous studies involving a bolus addition of H(2)O(2), a procedure that disrupts the cellular homeostasis. The results allowed us to define three phases for H(2)O(2)-induced apoptosis in Jurkat T-cells with reference to cytosolic steady state concentrations of H(2)O(2) [(H(2)O(2))(ss)]: (H(2)O(2))(ss) values below 0.7 microM elicited no effects; (H(2)O(2))(ss) approximately 0.7-3 microM induced apoptosis; and (H(2)O(2))(ss) > 3 microM yielded no additional apoptosis and a gradual shift towards necrosis as the mode of cell death were observed. H(2)O(2)-induced apoptosis was not affected by either BCNU, an inhibitor of glutathione reductase, or diamide, a compound that reacts both with low-molecular weight and protein thiols, or selenols. Glutathione depletion, accomplished by incubating cells either with buthionine sulfoximine or in cystine-free medium, rendered cells more sensitive to H(2)O(2)-induced apoptosis, but did not change the threshold and saturating concentrations of H(2)O(2) that induced apoptosis. Two unrelated metal chelators, desferrioxamine and dipyridyl, strongly protected against H(2)O(2)-induced apoptosis. It may be concluded that, under conditions of H(2)O(2) delivery that mimic in vivo situations, the oxidative event that triggers the induction of apoptosis by H(2)O(2) is a Fenton-type reaction and is independent of the thiol or selenium states of the cell.

2,2'-Dipyridyl↗
PubMedDate not supplied

Apoptosis in myocarditis and dilated cardiomyopathy: does enterovirus genome persistence protect from apoptosis? An endomyocardial biopsy study.

UNLABELLED: The purpose of this study was to examine the role of apoptosis in myocarditis and dilated cardiomyopathy. Apoptosis is an active energy-consuming mechanism of cell death in several cardiac diseases in different quality and quantity. METHODS: Endomyocardial biopsies from 81 patients with active (1) and chronic myocarditis (10), dilated cardiomyopathy with inflammation (DCMi; 10) and without inflammation (DCM; 20), with borderline myocarditis and positive PCR for cytomegalovirus-DNA (6), adenovirus-DNA, or enterovirus-RNA (7), and controls (17) were analysed. Apoptosis was detected by using the TUNEL method. The highest rate of apoptotic cardiocytes was found in active and chronic myocarditis. One patient with severe active myocarditis demonstrated 6.15% of apoptotic cardiocytes. Mean percentage of apoptotic cardiocytes in chronic myocarditis was significantly increased (0.61+/-1.25%) when compared to controls (0.01+/-0.04%, P<.05). Particularly, patients with cytomegalovirus-DNA persistence in borderline myocarditis had an elevated rate of apoptosis (0.34+/-0.68%, P<.05). Increased rates of apoptosis were found in borderline myocarditis with adenovirus-DNA persistence (0.20+/-0.57%) and in DCM (0.06+/-0.15%). Only a nonsignificant increase of apoptotic cardiocytes was found in DCMi (0.03+/-0.08%). No apoptosis was found in patients with enteroviral genome persistence in borderline myocarditis. CONCLUSIONS: Apoptosis of cardiac cells is increased in myocarditis and dilated cardiomyopathy, being highest in severe active myocarditis. Apoptosis thus contributes to cell death in active myocarditis and may play a role not to be neglected in dilated cardiomyopathy. Enteroviruses seem to have anti-apoptotic effects, because no apoptosis at all was found in the myocardium.

Apoptosis↗