Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Tibetan herbal remedy PADMA 28 revealed promising results to support treatment of atherosclerosis, Charot syndrome (intermittent claudication), chronic active hepatitis and infection of the respiratory tract. The remedy was confirmed to be closely linked with anti- and pro-oxidative properties in vitro. In this study, apoptogenic and survival effects of PADMA 28 were investigated in the T cell-derived lymphocytic leukaemia cell line CEM-C7H2. PADMA 28 led to a concentration-dependent inhibition of cell proliferation accompanied by the accumulation of CEM-C7H2 cells in subG1 phase, fragmentation of poly (ADP-ribose) polymerase (PARP) and nuclear body formation. Treatment with PADMA 28 rescued to some extent cells over-expressing Bcl-2 from apoptosis. This finding suggests that the mechanism of action of PADMA 28 may be via interference with Bcl-2 triggered survival pathways.
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PMID:Apoptosis induced by the Tibetan herbal remedy PADMA 28 in the T cell-derived lymphocytic leukaemia cell line CEM-C7H2. 1613 18

Here we determined which radiation-responsive genes were altered in radioresistant CEM/IR and FM3A/IR variants, which showed higher resistance to irradiation than parental human leukemia CEM and mouse mammary carcinoma FM3A cells, respectively and studied if radioresistance observed after radiotherapy could be restored by inhibition of protein kinase A. The expressions of DNA-PKcs, Ku70/80, Rad51 and Rad54 genes that related to DNA damage repair, and Bcl-2 and NF-kappaB genes that related to antiapoptosis, were up-regulated, but the expression of proapototic Bax gene was down-regulated in the radioresistant cells as compared to each parental counterpart. We also revealed that the combined treatment of radiation and the inhibitor of protein kinase A (PKA) to these radioresistant cells resulted in synergistic inhibition of DNA-PK, Rad51 and Bcl-2 expressions of the cells, and consequently restored radiosensitivity of the cells. Our results propose that combined treatment with radiotherapy and PKA inhibitor can be a novel therapeutic strategy to radioresistant cancers.
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PMID:Radiosensitization by targeting radioresistance-related genes with protein kinase A inhibitor in radioresistant cancer cells. 1639 22

Acute lymphoblastic leukemia (ALL), especially T-acute lymphoblastic leukemia (T-ALL), is a common childhood malignant neoplastic disorder. Chemotherapy agents, particularly those that can induce apoptosis, are the major intervening strategy in the treatment of ALL. In this study, we investigated in T-ALL cell line, CCRF-CEM, the in vitro cytotoxic effect and the mechanism of action of baicalin, a compound extracted from Scutellaria baicalensis Georgi and S. rivularis Benth (Labiateae). Results demonstrated that baicalin displayed a remarkable cytotoxic effect in CCRF-CEM, with an IC(50) value of 10.6 microg/ml. It triggered apoptotic effect by fragmentizing cellular DNA and arrested the cell cycle at G(0)/G(1) phase. Baicalin (37.5 microg/ml) had not effected the expression of p53 and Fas protein. It was shown to decline the expression of Bcl-2 (22.0 pg/ml), which consequently caused the loss (52.7%) of transmembrane potential (Delta Psi m) in the mitochondria after 72 hours of treatment. Baicalin (37.5 microg/ml) also elevated the amount of cytosolic cytochrome c (19.2 microg/ml), which finally triggered the activation of caspase-3 (50.1 pmol/min). In conclusion, baicalin was found to induce apoptosis in T-ALL cell lines through multiple pathways. This finding encourages further investigation of baicalin in its role as a potential candidate for chemotherapeutic agents in T-ALL.
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PMID:Baicalin-induced apoptosis is mediated by Bcl-2-dependent, but not p53-dependent, pathway in human leukemia cell lines. 1655 36

Permeability-glycoprotein (Pgp) positive cells are known to be encoded by the multidrug-resistance gene (MDR1), and characterized by a reduced ability to accumulate drugs. The vinblastin-resistant, Pgp positive CEM-VLB 1000 and its wild type (Pgp-negative and vinblastin-sensitive) counterpart CEM-T4 human leukemia cells, when treated with the alkaloid sanguinarine, were both found to undergo apoptosis at concentrations of 1.5 microg/ml and oncosis/blister cell death (BCD) at concentrations of 12.5 microg/ml. The aim of this study was to assess the ability of sanguinarine to overcome Pgp-mediated multidrug-resistance (MDR), and also to characterize the cell death processes of apoptosis and oncosis (or bimodal cell death) induced by sanguinarine in MDR cells. The cell death processes of apoptosis and oncosis in CEM-VLB 1000 and CEM-T4 cell lines were found to be qualitatively similar when assessed by light microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling, annexin-V-binding, trypan blue exclusion and western blot analysis. Western blotting revealed an increase in the Bax/Bcl-2 ratio and activation of caspase-3 in apoptosis but not oncosis in both cell lines. The Pgp-positive CEM-VLB 1000 cells and their wild type CEM-T4 cells were both equally sensitive to sanguinarine. Thus, sanguinarine may overcome the phenomenon of Pgp-mediated MDR by inducing apoptosis through increasing the Bax/Bcl-2 ratio and activating caspase-3, and oncosis, which involved neither.
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PMID:Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells. 1673 6

Serine/threonine phosphatase regulation of phosphorylation-mediated intracellular signaling controls a number of important processes in mammalian cells. In this study, we show that constitutively active protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase, is essential for T leukemia cell survival. Jurkat and CCRF-CEM T leukemia cells treated with the PP2A-selective inhibitor okadaic acid (OA) showed a dose- and time-dependent induction of apoptosis, as indicated by loss of mitochondrial transmembrane potential (delta psi(m)), cleavage-induced activation of caspase-3, -8, and -9, and DNA fragmentation. In addition, caspase-8 or caspase-9 inhibition with z-IETD-fmk or z-LEHD-fmk, respectively, largely prevented OA-induced apoptosis. Although OA treatment did not affect constitutive Bcl-2 expression, overexpression of Bcl-2 prevented both OA-induced DNA fragmentation and dissipation of delta psi(m). Furthermore, inhibition of caspase-3, -8, or -9 partially protected against OA-induced loss of delta psi(m). In addition, caspase-9 and caspase-3 inhibition largely prevented procaspase-3 and procaspase-8 cleavage, respectively, while caspase-8 inhibition partially interfered with procaspase-9 cleavage in OA-treated T leukemia cells. Thus, PP2A inhibition triggered the intrinsic pathway of apoptosis, which was enhanced by a mitochondrial feedback amplification loop. PP2A has also been implicated in the regulation of p38 mitogen-activated protein kinase (MAPK). Co-immunoprecipitation analysis revealed a physical association between the catalytic subunit of PP2A and p38 MAPK in T leukemia cells. Moreover, OA treatment caused p38 MAPK to be phosphorylated in a dose- and time-dependent fashion, indicating that PP2A prevented p38 MAPK activation. Although p38 MAPK activation usually promotes apoptosis, pharmacologic inhibition of p38 MAPK exacerbated OA-induced DNA fragmentation and loss of delta psi(m) in T leukemia cells, suggesting that, in this instance, the p38 MAPK signaling pathway promoted cell survival. Collectively, these findings indicate that PP2A and p38 MAPK have coordinate effects on signaling pathways that regulate the survival of T leukemia cells.
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PMID:Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase. 1684 42

Gallium nitrate is a metallodrug with clinical efficacy in non-Hodgkin's lymphoma. Its mechanisms of antineoplastic action are not fully understood. In the present study, we investigated the roles of transferrin receptor (TfR) targeting and apoptotic pathways in gallium-induced cell death. Although DoHH2 lymphoma cells displayed a 3-fold lower number of TfRs than CCRF-CEM lymphoma cells, they were 3- to 4-fold more sensitive to gallium nitrate. Despite a lower TfR expression, DoHH2 cells had greater TfR cycling and iron and gallium uptake than CCRF-CEM cells. In other lymphoma cell lines, TfR levels per se did not correlate with gallium sensitivity. Cells incubated with gallium nitrate showed morphologic changes of apoptosis, which were decreased by the caspase inhibitor Z-VAD-FMK and by a Bax-inhibitory peptide. Cells exposed to gallium nitrate released cytochrome c from mitochondria and displayed a dose-dependent increase in caspase-3 activity. An increase in active Bax levels without accompanying changes in Bcl-2 or Bcl-X(L) was seen in cells incubated with gallium nitrate. The endogenous expression of antiapoptotic Bcl-2 was greater in DoHH2 cells than in CCRF-CEM cells, suggesting that endogenous Bcl-2 levels do not correlate with cell sensitivity to gallium nitrate. Gallium-induced apoptosis was enhanced by the proteasome inhibitor bortezomib. Our results suggest that TfR function rather than TfR number is important in gallium targeting to cells and that apoptosis is triggered by gallium through the mitochondrial pathway by activating proapoptotic Bax. Our studies also suggest that the antineoplastic activity of combination gallium nitrate and bortezomib warrants further investigation.
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PMID:Gallium-induced cell death in lymphoma: role of transferrin receptor cycling, involvement of Bax and the mitochondria, and effects of proteasome inhibition. 1712 30

Ceramide, a long chain sphingolipid that is generated intracellularly upon hydrolysis of membrane-associated sphingomyelin, has recently been implicated as a second messenger-like molecule that is produced distal to ligation of the tumour necrosis factor receptor type 1 (TNFR1), as well as the related Fas (CD95/Apo-1) molecule. It is well established that ligation of TNFR1 or Fas leads to apoptosis in most cases. Furthermore, it has also recently been demonstrated that exposure to cell-permeable synthetic ceramides can result in apoptosis in many cases. These and other observations have led to the hypothesis that accumulation of intracellular ceramide may be a common element of several pathways that result in apoptosis. Here we show that exposure to synthetic ceramides triggers apoptosis in the human T lymphoblastoid cell lines, CEM and Jurkat, and that overexpression of the apoptosis-repressor protein, Bcl-2, renders these cells resistant to the apoptosis-inducing effects of ceramide, as well as to several other stimuli. Since exposure to ceramides can result in either cell proliferation, differentiation, cycle arrest, or death, the level of Bcl-2 expression in a cell may be an important factor in determining the outcome of signals that result in intracellular generation of this sphingolipid.
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PMID:Inhibition of ceramide-induced apoptosis by Bcl-2. 1718 30

We have recently reported that thapsigargin (TG), a specific endoplasmic reticulum (ER)-associated Ca(2+)-ATPase inhibitor, induces apoptosis in mouse lymphoma cells. In view of recent evidence that the imidazole antifungals econazole (EC) and miconazole (MC) inhibit TG-sensitive Ca(2+)-ATPase activity in normal rat thymocytes, we investigated the effect of these agents on intracellular Ca(2+) homeostasis and cell survival in WEHI7.2 mouse lymphoma cells and human CEMT-cell leukemia cells. In this report, we demonstrate that MC treatment releases Ca(2+) from the TG-sensitive ER pool of WEHI7.2 cells. MC induced apoptosis, based on morphological and biochemical criteria, and on inhibition by the Bcl-2 oncogene. Moreover, intracellular Ca(2+) changes induced by MC treatment were inhibited by overexpression of Bcl-2. In addition to inducing cell death in WEHI7.2 cells, MC induced apoptosis in the glucocorticoid sensitive and resistant human T-cell leukemia lines, CEM-C7 and CEM-C1 respectively, in normal thymocytes and in normal lymphocytes. Based on their apoptosis-inducing activity, imidazole derivatives should be explored as potential immunosuppressive and/or chemotherapeutic agents.
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PMID:Imidazole antifungals Miconazole and Econazole induce apoptosis in mouse lymphoma and human T cell leukemia cells: regulation by Bcl-2 and potential role of calcium. 1718 Jan 2

Doxorubicin (DOX) selection of CCRF-CEM leukaemia cell line resulted in multidrug resistance (MDR) CEM/A7R cell line, which overexpresses MDR, 1 coded P-glycoprotein (Pgp). Here, we report for the first time that oncoprotein Cripto, a founding member of epidermal growth factor-Cripto-FRL, 1-Criptic family is overexpressed in the CEM/A7R cells, and anti-Cripto monoclonal antibodies (Mab) inhibited CEM/A7R cell growth both in vitro and in an established xenograft tumour in severe combined immunodeficiency mice. Cripto Mab synergistically enhanced sensitivity of the MDR cells to Pgp substrates epirubicin (EPI), daunorubicin (DAU) and non-Pgp substrates nucleoside analogue cytosine arabinoside (AraC). In particular, the combination of anti-Cripto Mab at less than 50% of inhibition concentrations with noncytotoxic concentrations of EPI or DAU inhibited more than 90% of CEM/A7R cell growth. Cripto Mab slightly inhibited Pgp expression, and had little effect on Pgp function, indicating that a mechanism independent of Pgp was involved in overcoming MDR. We demonstrated that anti-Cripto Mab-induced CEM/A7R cell apoptosis, which was associated with an enhanced activity of the c-Jun N-terminal kinase/stress-activated protein kinase and inhibition of Akt phosphorylation, resulting in an activation of mitochondrial apoptosis pathway as evidenced by dephosphorylation of Bad at Ser136, Bcl-2 at Ser70 and a cleaved caspase-9.
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PMID:Anti-Cripto Mab inhibit tumour growth and overcome MDR in a human leukaemia MDR cell line by inhibition of Akt and activation of JNK/SAPK and bad death pathways. 1734 96

Altered or deficient activation of apoptosis signalling pathways may contribute to drug resistance. Here, we assess the role of apoptotic mediators in eliciting an anti-proliferative response to paclitaxel (PTX) in a T cell acute lymphoblastic leukemia (ALL) cell line CEM and its epothilone-paclitaxel resistant sub-line CEM/dEpoB300. Furthermore, the cellular response to PTX was compared to those elicited by cells in response to treatment with albendazole (ABZ; a microtubule depolymerizing agent). In cell proliferation studies, CEM cells were sensitive to both PTX and ABZ, while the CEM/dEpoB300 cells were highly resistant to PTX (IC(50) 2.86 nM versus 30.26 nM, respectively). In contrast, the resistant cells showed a 2-fold increase in sensitivity to ABZ (0.32 microM in CEM compared to 0.16 microM in CEM/dEpoB300). Analysis of caspase-3 activity and cytochrome c release in response to PTX or ABZ treatment (24, 48 and 72 h) revealed that, compared to the parent cells, the resistant cells have diminished response to PTX and enhanced response to ABZ. A similar pattern was observed for the pro-apoptotic protein Bax. Levels of the anti-apoptotic protein Bcl-2 was highly elevated in CEM/dEpoB300 cells and in these cells, ABZ was more effective in lowering the Bcl-2 levels than PTX. Similarly, ABZ treatment led to profound down regulation of the Mcl-1 protein. These results reveal for the first time, the changes in apoptotic mediators following development of resistance to PTX in an ALL cell and the significantly increased sensitivity of these PTX resistant cells to ABZ.
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PMID:Epothilone-paclitaxel resistant leukemic cells CEM/dEpoB300 are sensitive to albendazole: Involvement of apoptotic pathways. 1756 Sep 63


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