Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methyl mercury neurotoxicity is associated with a broad range of neuropathologic and biochemical disturbances which include induction of oxidative injury. Treatment of the hypothalamic neural cell line GT1-7 with 10 microM methyl mercury (MeHg) for 3 h resulted in increased formation of reactive oxygen species (ROS), and decreased levels of reduced glutathione (GSH), associated with 20% cell death. Cells transfected with an expression construct for the anti-apoptotic proto-oncogene, bcl-2, displayed attenuated ROS induction and negligible cell death. Twenty-four-h exposure to 5 microM MeHg killed 56% of control cells, but only 19% of bcl-2-transfected cells. By using diethyl maleate to deplete cells of GSH, we demonstrate that the differential sensitivity to MeHg was not due solely to intrinsically different GSH levels. The data suggest that MeHg-mediated cell killing correlates more closely with ROS generation than with GSH levels and that bcl-2 protects MeHg-treated cells by suppressing ROS generation.
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PMID:bcl-2 expression decreases methyl mercury-induced free-radical generation and cell killing in a neural cell line. 794 May 96

Cytosine arabinoside is usually considered to be lethal by incorporation into DNA followed by chain termination. Recently, we have reported that the radical scavenger N-acetyl-cysteine (NAC) protects cultured clonogenic AML blast cells from the lethal affects of Ara-C if given before the drug. This observation provides indirect evidence that toxic reactive oxygen intermediates (ROI) are generated in AML blast cells following Ara-C-induced damage to DNA. In the present paper we present evidence in support of this hypothesis. Using flow cytometry and multiple fluorescent probes for live cell function, we have mapped a sequence of discrete stages that occur during Ara-C cytotoxicity. An early event was the increased generation of ROI. Initially this oxidative stress was countered by an increase in the cellular content of reduced glutathione (GSH), but cells then underwent an abrupt transition to a state characterized by low GSH and very high ROI generation indicative of collapse of cellular redox balance. Next, the capacity to maintain low intracellular ionized calcium was lost, probably due to lipid peroxidation at membrane sites of calcium regulation. Finally, surface membrane integrity was lost. Concurrent measurements of clonogenic cell survival insured the relevance of these flow cytometry measurements to the stem cell population. We used OCI/AML-2 cells transfected with bcl-2 to look for the place in this sequence where bcl-2 protein protects cells against apoptosis; bcl-2 transfectants showed an increase in ROI generation similar to controls, but were able to maintain GSH levels in the face of this oxidative stress. We conclude that oxidative stress plays a major role in Ara-C toxicity, and that bcl-2 protein protects cells by maintaining cellular redox balance in a reducing state. These studies complement previous work showing how regulators of AML growth affect the sensitivity of blast cells to Ara-C by changing the concentration or stability of bcl-2 protein.
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PMID:Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2. 868 94

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase in not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.
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PMID:Chlorambucil in chronic lymphocytic leukemia: mechanism of action. 903 Oct 99

It has been demonstrated that nitric oxide (NO) can promote apoptosis in human cancer cells. To test the protective effects of antioxidants (N-acetyl-L-cysteine (LNAC) and free-radical spin traps (5,5-dimethyl-1-pyrroline N-oxide and 2,2,6,6,-tetramethyl-1-piperidinyloxy) against NO-induced apoptosis, a human colon cancer cell line (COLO 205) was treated with NO, and its survival rate was evaluated both with and without antioxidant therapy. LNAC arrested the development of progression of apoptosis in COLO 205 cells in a dose-dependent manner, promoted long-term survival, and prevented the internucleosomal DNA cleavage induced by NO. The intracellular level of glutathione (GSH) was found to be elevated in cells after exposure to LNAC. The bax protein levels were elevated by NO treatment, and this effect was blocked by LNAC. On the other hand, the bcl-2 oncoprotein level in the LNAC-pretreated cells was significantly elevated in a time-dependent manner compared to cells that received NO pretreatment. In summary, our results suggest that the protective effect of LNAC may be linked to its inducement of increases in cellular GSH and bcl-2 protein levels and to its suppression of cellular bax protein in treated cells.
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PMID:Suppression of nitric oxide-induced apoptosis by N-acetyl-L-cysteine through modulation of glutathione, bcl-2, and bax protein levels. 921 Sep 57

Bcl-xL and bax are bcl-2-related genes whose protein products either inhibit or promote apoptosis. Oxidative damage, including the loss of glutathione, has been implicated in the induction of apoptosis. The ability of the Bcl proteins to affect GSH was assessed in control, bax- and bcl-xL-transfected FL5.12 cells [an interleukin (IL)-3-dependent murine prolymphocytic cell line]. Overall levels of GSH were approximately the same in control and bcl-xL transfectants during the 6 h incubation period, although levels increased in bcl-xL transfectants 24 h after replating. GSH in cells overexpressing bax was reduced by approximately 36%. There were no consistent differences between these cell lines in the activities of superoxide dismutase, catalase, glutathione peroxidase or glutathione reductase. Following IL-3 withdrawal, a condition known to cause apoptosis in these cells, a rapid loss of intracellular GSH occurred in control and bax transfectants, which preceded the onset of apoptosis. GSH depletion could not be attributed to intracellular oxidation but rather seemed to occur due to a translocation out of the cell. Cells overexpressing bcl-xL did not lose significant amounts of GSH upon withdrawal of IL-3, and no apoptosis was evident. These results suggest a possible role for GSH in the mechanism by which bcl-xL prevents cell death.
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PMID:Bcl-xL overexpression attenuates glutathione depletion in FL5.12 cells following interleukin-3 withdrawal. 923 Jan 8

Flupirtine, trade name Katadolon, is a centrally acting nonopioid analgesic that has recently been found to display cytoprotective activity in vitro and in vivo on neurons induced to undergo apoptosis. This report shows that the PrP106-126 fragment of the prion protein, which is the likely etiological agent for a series of encephalopathies, is toxic to cortical neurons in vitro. Simultaneously, PrP106-126 influences the molecular GSH content and the bcl-2 expression in neurons. Significant toxicity (32% reduction in cell viability) was observed at a concentration of 50 microM of the peptide after 9 days of incubation, while at higher concentrations toxicity increased to 70%. Neurotoxicity was greatly reduced following coincubation with 1 to 3 microg/ml flupirtine. Concomitant with PrP106-126-mediated cytotoxicity, glutathione (GSH) content fell by > 70% with respect to untreated controls. This decrease in GSH level was strongly blocked by flupirtine under incubation conditions that reduce cell toxicity. In addition to normalizing GSH content, flupirtine induced the expression of the anti-apoptotically acting proto-oncogene bcl-2. Based on these in vitro data and on the favorable pharmacokinetic profile of the drug, we strongly suggest that flupirtine may prove useful for treatment of patients with prion disease.
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PMID:Effect of flupirtine on Bcl-2 and glutathione level in neuronal cells treated in vitro with the prion protein fragment (PrP106-126). 934 76

Immunolocalization of glutathione-peroxidase (GSH-PO), apoptosis and bcl-2 protein in the rat ventral prostate was investigated in the presence or absence of androgen. Male Sprague-Dawley rats were divided into four experimental groups. Group 1 consisted of intact controls. In group 2, rats were sacrificed two days after castration. In groups 3 and 4, rats were administered subcutaneously 1 mg/animal of testosterone-propionate daily for three or seven days at two days after castration. The intensity of GSH-PO staining in the glandular epithelial cells of the ventral prostate was remarkably decreased after castration (Group 2), and it clearly recovered when testosterone was administered (Groups 3 and 4) to the castrated rats. The prostatic GSH-PO mRNA levels were diminished in the castrated rat ventral prostate but greatly increased by testosterone (Groups 3 and 4). Furthermore, castration (Group 2) induced apoptosis in the prostatic glandular epithelial calls and the apoptosis was reduced by testosterone-administration (Groups 3 and 4) to the castrated rats. In groups 3 and 4, expression of bcl-2 protein was clearly detected in the glandular epithelial cells of the ventral prostate. These findings strongly suggested that expression of GSH-PO and bcl-2 protein in the glandular epithelial cells of the rat ventral prostate is testosterone-dependent.
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PMID:Expression of glutathione-peroxidase (GSH-PO) in the rat ventral prostate--effect of castration and administration of testosterone. 1547 42

We hypothesized that unexplained increases in nucleoside triphosphates (NTP) observed by 31P magnetic resonance spectroscopy (MRS) after treatment of tumours by DNA-damaging agents were related to chemotherapy-induced up-regulation of the bcl-2 gene and DNA damage prevention and repair processes. To test this hypothesis, we treated HT-29 cells with 10(-4) M nitrogen mustard (HN2) and performed sequential perchloric acid extractions in replicate over 0-18 h. By reference to an internal standard (methylene diphosphonic acid), absolute changes in 31P-detectable high-energy phosphates in these extracts were determined and correlated with changes in bcl-2 protein levels, cell viability, cell cycle, apoptosis and total cellular glutathione (GSH) (an important defence against DNA damage from alkylating agents). After HN2 administration, bcl-2 protein levels in the HT-29 cell line rose at 2 h. Cell viability declined to 25% within 18 h, but apoptosis measured using fluorescence techniques remained in the 1-4% range. Increased cell division was noted at 4 h. Two high-energy interconvertible phosphates, NTP (P < or = 0.006) and phosphocreatine (PCr) (P < or = 0.0002), increased at 2 h concurrently with increased levels of bcl-2 protein and glutathione. This study demonstrates that bcl-2 and glutathione are up-regulated by HN2 and links this to a previously unexplained 31P MRS phenomenon: increased NTP after chemotherapy.
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PMID:Nitrogen mustard up-regulates Bcl-2 and GSH and increases NTP and PCr in HT-29 colon cancer cells. 965 54

Alveolar epithelial cell (AEC) injury and repair are important in the pathogenesis of oxidant-induced lung damage. Keratinocyte growth factor (KGF) prevents lung damage and mortality in animals exposed to various forms of oxidant stress, but the protective mechanisms are not yet established. Because DNA strand break (DNA-SB) formation is one of the earliest cellular changes that occurs after cells are exposed to an oxidant stress, we determined whether KGF reduces H2O2-induced pulmonary toxicity by attenuating AEC DNA damage. KGF (10-100 ng/ml) decreased H2O2 (0.05-0.5 mM)-induced DNA-SB formation in cultured A549 and rat alveolar type II cells measured by an alkaline unwinding, ethidium bromide fluorometric technique. The protective effects of KGF were independent of alterations in catalase, glutathione (GSH), or the expression of bcl-2 and bax, two protooncogenes known to regulate oxidant-induced apoptosis. Actinomycin D and cycloheximide abrogated protective effects of KGF. Furthermore, protection by KGF was completely blocked by 1) genistein, a tyrosine kinase inhibitor; 2) staurosporine and calphostin C, protein kinase C (PKC) inhibitors; and 3) aphidicolin, butylphenyl dGTP, and 2',3'-dideoxythymidine 5'-triphosphate, inhibitors of DNA polymerase. We conclude that KGF attenuates H2O2-induced DNA-SB formation in cultured AECs by mechanisms that involve tyrosine kinase, PKC, and DNA polymerases. These data suggest that the ability of KGF to protect against oxidant-induced lung injury is partly due to enhanced AEC DNA repair.
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PMID:Keratinocyte growth factor promotes alveolar epithelial cell DNA repair after H2O2 exposure. 975 11

Cholangiocytes are the target of a group of liver diseases termed the cholangiopathies that include conditions characterized by periductal inflammation and cholangiocyte apoptosis. Because inflammation is associated with oxidative stress, we developed the hypothesis that cholangiocytes exposed to oxidative stress will be depleted of endogenous cytoprotective molecules, leading to cholangiocyte apoptosis. To begin to test this hypothesis, we explored the relationships among glutathione (GSH) depletion, expression of Bcl-2 (a protooncogene that inhibits apoptosis), and apoptosis in a nonmalignant human cholangiocyte cell line. Monolayers of human bile duct epithelial cells, derived from normal liver and immortalized by SV40 transformation, were depleted of GSH using buthionine sulfoximine (BSO). Bcl-2 expression was assessed by quantitative immunoblot analysis, and apoptosis quantified by fluorescence microscopy using the DNA binding dye 4', 6'-diamidino-2-phenylindole. Bcl-2 message was assessed by RNase protection assay, and Bcl-2 protein synthesis and half-life by pulse-chase analysis. Exposure of human cholangiocytes in culture to BSO reduced GSH levels by 93 +/- 3% (P < 0.01). In addition, treatment of cholangiocytes with BSO reduced Bcl-2 levels by 87 +/- 2% (P < 0.01) and was associated with a time-dependent increase in the number of cells undergoing apoptosis; approximately 11 +/- 1% of cultured cells demonstrated morphological changes of apoptosis by 72 h compared with 1.5 +/- 0.1% in untreated cholangiocytes (P < 0. 01). Maintenance of GSH levels by addition of glutathione ethyl ester in the presence of BSO blocked the BSO-associated increase in apoptosis in BSO-treated cholangiocytes and also prevented the decrease in Bcl-2 protein. BSO treatment of cholangiocytes did not change steady-state levels of bcl-2 mRNA or Bcl-2 protein synthesis. However, Bcl-2 protein half-life decreased 57% in BSO-treated vs. untreated cells. Our results using a human cholangiocyte cell line demonstrate that reduction in the cellular levels of an antioxidant such as GSH results in increased degradation of Bcl-2 protein and an increase in apoptosis. These data provide a mechanistic link between the consequences of oxidative stress and cholangiocyte apoptosis, an observation that may be important in the pathogenesis of the inflammatory cholangiopathies.
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PMID:Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes. 975 6


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