Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P30536 (PBS)
9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One critical step of the apoptotic process is the opening of the mitochondrial permeability transition (PT) pore leading to the disruption of mitochondrial membrane integrity and to the dissipation of the inner transmembrane proton gradient (Delta Psim). The mitochondrial PT pore is a polyprotein structure which is inhibited by the apoptosis-inhibitory oncoprotein Bcl-2 and which is closely associated with the mitochondrial benzodiazepine receptor (mBzR). Here we show that PK11195, a prototypic ligand of the 18-kDa mBzR, facilitates the induction of Delta Psim disruption and subsequent apoptosis by a number of different agents,including agonists of the glucocorticoid receptor,chemotherapeutic agents (etoposide, doxorubicin),gamma irradiation, and the proapoptotic second messenger ceramide. Whereas PK11195 itself has no cytotoxic effect, it enhances apoptosis induction by these agents. This effect is not observed for benzodiazepine diazepam, whose binding site in the mBzR differs from PK11195. PK11195 partially reverses Bcl-2 mediated inhibition of apoptosis in two different cell lines. Thus, transfection-enforced Bcl-2 overexpression confers protection against glucocorticoids and chemotherapeutic agents, and this protection is largely reversed by the addition of PK11195. This effect is observed at the level of Delta Psim dissipation as well as at the level of nuclear apoptosis. To gain insights into the site of action of PK11195, we performed experiments on isolated organelles. PK11195 reverses the Bcl-2-mediated mitochondrial retention of apoptogenic factors which cause isolated nuclei to undergo apoptosis in a cell-free system. Mitochondria from control cells, but not mitochondria from Bcl-2-overexpressing cells, readily release such apoptogenic factors in response to atractyloside, a ligand of the adenine nucleotide translocator. However, control and Bcl-2-overexpressing mitochondria respond equally well to a combination of atractyloside and PK11195. Altogether, these findings indicate that PK11195 abolishes apoptosis inhibition by Bcl-2 via a direct effect on mitochondria. Moreover, they suggest a novel strategy for enhancing the susceptibility of cells to apoptosis induction and, concomitantly, for reversing Bcl-2-mediated cytoprotection.
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PMID:PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection. 963 84

The molecular mode of action of arsenic, a therapeutic agent employed in the treatment of acute promyelocytic leukemia, has been elusive. Here we provide evidence that arsenic compounds may act on mitochondria to induce apoptosis. Arsenite induces apoptosis accompanied by a loss of the mitochondrial transmembrane potential (Delta Psim). Inhibition of caspases prevents the arsenite-induced nuclear DNA loss, but has no effect on the Delta Psim dissipation and cytolysis induced by arsenite. In contrast, Bcl-2 expression induced by gene transfer prevents all hallmarks of arsenite-induced cell death, including the Delta Psim collapse. PK11195, a ligand of the mitochondrial benzodiazepine receptor, neutralizes this Bcl-2 effect. Mitochondria are required in a cell-free system to mediate arsenite-induced nuclear apoptosis. Arsenite causes the release of an apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space. This effect is prevented by the permeability transition (PT) pore inhibitor cyclosporin A, as well as by Bcl-2, which is known to function as an endogenous PT pore antagonist. Arsenite also opens the purified, reconstituted PT pore in vitro in a cyclosporin A- and Bcl-2-inhibitible fashion. Altogether these data suggest that arsenite can induce apoptosis via a direct effect on the mitochondrial PT pore.
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PMID:Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. 1036 41

The effects of HIV-1 Tat protein on mitochondria membrane permeability and apoptosis were analysed in lymphoid cells. In this report we show that stable-transfected HIV-Tat cells are primed to undergo apoptosis upon serum withdrawal. This effect was observed in both the Jhan T cell line and the K562 cells, the latter expressing the bcr-abl chimeric gene, which confers resistance to apoptosis induced by different stimuli. Using a cytofluorimetric approach we have determined that serum withdrawal induces a disruption of the transmembrane mitochondrial potential (Deltapsim) followed by an increase of reactive oxygen species (ROS) and the subsequent DNA nuclear loss in K562-Tat cells but not in the K562-pcDNA cell line. These pre-apoptotic events were associated with the cleavage of the caspase-3, while the expression of Bcl-2, Bcl-XL and Bax proteins was not affected by the presence of Tat. Regardless of the steady state of the Bax protein, we found that in both K562 and K562-Tat cells, this protein is located in the nucleus, but after serum withdrawal its localization was mainly in the cytoplasm. The activity of caspase-3 detected in K562-Tat cells after serum withdrawal paralleled with the mitochondria permeability transition. Nevertheless, in Jhan-Tat cells the inhibition of this caspase with the specific inhibitor, z-DEVD-cmk, did not affect the disruption of the mitochondria potential induced by serum withdrawal. Interestingly, we found that HIV-Tat protein accumulates at the mitochondria in the K562-Tat cells cultured under low serum conditions, and this mitochondrial localization correlated with the Deltapsim disruption detected in these cells. In addition, HIV-1 Tat protein synergies with protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepine receptor, in the induction of apoptosis in both Jhan and K562 cells. Thus, HIV-1 Tat protein may induce apoptosis by a mechanism that involves mitochondrial PT and may contribute to the lymphocyte depletion seen in AIDS patients.
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PMID:Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms. 1060 13

Mitochondrial membrane permeabilization is a critical event in the process leading to physiologic or chemotherapy-induced apoptosis (programmed cell death). This permeabilization event is, at least in part, under the control of the permeability transition pore complex (PTPC). Oncoproteins from the Bcl-2 family and tumor suppressor proteins from the Bax family interact with PTPC to inhibit or facilitate membrane permeabilization, respectively. Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic alpha-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. However, stabilization of the mitochondrial membrane by antiapoptotic Bcl-2-like proteins reduces the cytotoxic potential of most of these drugs. Targeting of specific PTPC components may overcome this Bcl-2-mediated apoptosis inhibition. One strategy involves cross-linking of critical redox-sensitive thiol groups within the PTPC; another involves the use of ligands to the mitochondrial benzodiazepine receptor. Thus, the design of mitochondrion-targeted cytotoxic drugs may constitute a novel strategy for overcoming apoptosis resistance.
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PMID:Mitochondrion as a novel target of anticancer chemotherapy. 1088 May 47

Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. After 72 h exposure of human pancreatic islets to a cytotoxic cytokine combination of interleukin 1 beta (50 U/ml), tumor necrosis factor alpha (1,000 U/ml), and interferon gamma (1,000 U/ml), an increase of cell death vs. control islets was demonstrated by TUNEL and cell death detection ELISA method. Islet death was associated with apoptosis and mitochondrial swelling as evidenced by electron microscopy. This effect was correlated with a marked decrease of Bcl-2 mRNA expression (without any major change of Bax mRNA) and a marked increase of inducible nitric oxide synthase mRNA. Since peripheral benzodiazepine receptors constitute the aspecific mitochondrial permeability transition pore, and that it has been suggested to be involved in cytokine-induced cell death, we evaluated the effects of the cytotoxic cytokines on PBR density and mRNA expression. We demonstrated that cytokine treatment of human islets induced an increase of maximum density of (3)H1-(2-chlorophenyl-N-methyl-1-methylpropyl)-3- isoquinolinecarboxamide binding sites, (5,110+/-193 vs. 3,421+/-336 fmol/mg proteins, P<0.05) with no significant change in the affinity constant value (9.45+/-0.869 vs. 8.7+/-1.159 nM). Moreover, an increase of the expression of peripheral benzodiazepine receptor mRNA was observed, suggesting an increased transcription from the coding gene. These results suggest a possible role of peripheral benzodiazepine receptors in the organism response to tissue damage associated with inflammatory mediator production.
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PMID:Upregulation of mitochondrial peripheral benzodiazepine receptor expression by cytokine-induced damage of human pancreatic islets. 1181 68

Opening of the permeability transition (PT) pore is a central feature of apoptosis induction by chemical stress. One component of the PT pore, the mitochondrial benzodiazepine receptor (mBzR), has recently received attention for its potential role in modulating PT pore function. Specifically, antagonistic ligands of the mBzR, such as 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (PK11195), have been shown to sensitize Bcl-2 overexpressing cells to apoptosis induction by facilitating the opening of the PT pore and the subsequent loss of mitochondrial membrane potential (Deltapsim). We examined whether PK11195 can sensitize EW36, a human B-cell lymphoma cell line that over-expresses Bcl-2, to apoptosis induction and mitochondrial depolarization by environmental chemicals including mitochondrial toxicants. We found that, although EW36 cells are refractory to apoptosis induction by antimycin A, rotenone, pyridaben, alachlor, and carbonyl cyanide m-chlorophenylhydrazone (mClCCP), they are dramatically sensitized to induction of apoptosis by low concentrations of these same agents following pre-treatment with PK11195. The sensitization of EW36 cells is accompanied by a rapid and extensive loss of Deltapsim within a few hours following chemical exposure. Furthermore, using sodium arsenite, we examined the role of the c-Jun N-terminal kinase (JNK) pathway and protein synthesis in apoptosis induction in EW36. We found that, unlike untreated cells, EW36 cells treated with PK11195 no longer show an association of JNK pathway activation with apoptosis induction. Importantly, PK11195 eliminates a requirement for protein synthesis in chemically induced apoptosis in EW36 cells. These results show significant drug-mediated alteration of cell sensitivity and JNK pathway activation to environmental chemicals and mitochondrial toxicants, following ligation of the mBzR.
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PMID:Reversal of Bcl-2-mediated resistance of the EW36 human B-cell lymphoma cell line to arsenite- and pesticide-induced apoptosis by PK11195, a ligand of the mitochondrial benzodiazepine receptor. 1475 1

Mitochondria plays a central role in apoptotic cell death. The intermembrane space of mitochondria contains a number of soluble molecules whose release from the organelle to the cytosol or the nucleus induces cell death. Thus, molecules that directly trigger mitochondria membrane permeabilisation are efficient cytotoxic drugs. Mitochondria is one of the cellular targets for commonly used epipodophyllotoxins, adenine deoxynucleoside analogs and taxanes as well as recently developped agents such as the pentacyclic triterpene betulinic acid and the lymphotoxic agent FTY720. Most informations on anthracyclines point to the mitochondrial membrane as the main target of cardiotoxicity. Mitochondria is also a target for arsenite trioxide, an old cytotoxic agent recently used for treating acute promyelocytic leukemia, lonidamine, a dichlorinated derivative of indazole-3-carboxylic acid developped as a chemosensitizer, the retinoic acid receptor gamma activator CD437 and nitric oxide (NO). Recently, cytotoxic drugs have been specifically designed to directly affect the mitochondrial function. These include the positively charged alpha-helical peptides, which are attracted to and disrupt the negatively charged mitochondrial membrane, thus inducing mammalian cell apoptosis when targeted intracellularly. Various strategies have been proposed also to directly inhibit Bcl-2 and related anti-apoptotic proteins, including antisense oligonucleotides (e.g. Genasense, currently tested in phase III trials), small molecules that mimic the BH3 dimerization domain of these proteins and kinase inhibitors. Ligands of the mitochondrial benzodiazepine receptor such as the isoquinolone carboxamide derivative PK11195 also overcome the membrane-stabilizing effect of Bcl-2, whereas the adenosine nucleotide translocator (ANT) and the mitochondrial DNA are two other potential cellular targets for cytotoxic agents. Potentially, new compounds directly targeting the mitochondria may be useful in treating hematological malignancies. The challenge is now to selectively target these mitochondria permeabilizing agents to malignant cells. This review briefly summarizes the role of the mitochondria in cell death and describes these various strategies for targeting the mitochondria to induce apoptosis.
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PMID:Mitochondria as a target for inducing death of malignant hematopoietic cells. 1276 32

Adoptive immunotherapy with tumor-specific T cells has emerged as a valid approach for prevention or treatment of diseases, such as melanoma and EBV-associated lymphoma. As interleukin (IL) 15 promotes survival of CD8(+) memory CTLs, we hypothesized that it could be used to enhance antitumor immunity in vivo through the maintenance of adoptively transferred memory CTL. To test this, we treated mice bearing P1A(+) tumors with adoptively transferred T cells possessing a transgenic Valpha8(+) T-cell receptor specific for the P1A tumor antigen (called P1CTL). Mice were then randomized to receive daily low-dose IL-15 (0.5 microg/day) or PBS. Mice receiving the transgenic P1CTL and IL-15 experienced a significantly delayed tumor relapse or complete tumor regression (P < 0.002 compared with PBS), with a striking persistence of the CD8(+) Valpha8(+) P1CTL compared with mice receiving the CD8(+) Valpha8(+) P1CTL and PBS vehicle (26.3 versus 5.1% P < 10(-5)). Animals exhibiting complete tumor regression had a significant population of CD8(+) Valpha8(+) P1CTL (46%) that persisted with IL-15 treatment until 140 days after adoptive transfer and successfully defended them against tumor rechallenge without IL-15. Low-dose IL-2 afforded no protection over vehicle and resulted in lower percentages of T cells with an activated memory phenotype, lower Bcl-2 expression, and lower ex vivo antitumor cytotoxicity compared with mice treated with IL-15. Collectively, the data support the notion that exogenous low-dose IL-15 therapy can enhance and even reverse the limited efficacy of adoptively transferred tumor-specific T-cell therapy and may do so in a fashion that is superior and distinct from exogenous IL-2 therapy.
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PMID:Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2. 1552 Feb 17

Flavonoids, which are main constituents of herbal medicines, have been reported to inhibit the growth of Helicobacter pylori (HP). Therefore, to evaluate the anti-HP activity of some flavonoids (flavanols, flavones, flavonols and isoflavonoids), their effects on the growth and vacuolation of HP as well as the infective properties of HP against HeLa cells were investigated. Catechins, quercetin and naringenin weakly inhibited the growth of HP, but all tested compounds did not inhibit HP infection into KATO III cells and HP urease activity. Quercetin and naringenin inhibited HP VacA vacuolation in HeLa cells with IC (50) values of 0.046 and 0.36 mM, respectively. Quercetin also inhibited procaspase-3 activation to caspase-3 in HeLa cells induced by HP VacA toxin, which may induce cell death via the proteolytic activation of a cascade of caspases. However, quercetin did not affect Bax and Bcl-2 protein levels. Based on these findings, quercetin may improve gastric cell death by inhibiting apoptotic signaling by HP VacA toxin. Abbreviations. HP: Helicobacter pyloriBSA:bovine serum albumin ESL:enhanced chemiluminescence MIC:minimum inhibitory concentration MTT:methylthiazolyldiphenyl-tetrazolium bromide PBS:phosphate-buffered saline VacA:Vacuolating cytotoxin.
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PMID:In vitro inhibitory effect of flavonoids on growth, infection and vacuolation of Helicobacter pylori. 1577 May 37

Cancer cells that express excessive levels of Bcl-2 pose a major problem in the delivery of curative therapy. Most treatments for such cancer involve chemotherapy to induce the apoptotic process. While these therapies often result in disease control for periods of time, failure to initiate apoptosis as a result of acquired resistance limits the effectiveness of treatment for many common hematopoietic and solid malignancies, and ultimately death from the malignancy still occurs. Various anti-apoptotic proteins of the Bcl-2 family that localize to the mitochondria appear to be involved in this resistance mechanism. However, recent advances in the understanding of malignant cell biology, achieved through both genomics and proteomics, have made it possible to explore novel approaches directed at re-establishing sensitivity to chemotherapy, presenting an attractive strategy for cancer treatment. In this article we discuss how this may be achieved by lowering Bcl-2 anti-apoptotic protein expression using antisense oligonucleotides or, alternatively, by functionally antagonizing Bcl-2 using ligands of the mitochondrial benzodiazepine receptor.
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PMID:Unraveling biologic therapy for Bcl-2-expressing malignancies. 1579 40


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