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)

Mitochondrial damage with release of cytochrome c is implicated in cell death signalling pathways. To examine mitochondrial function in apoptotic cells, we applied high-resolution respirometry to human leukemia cells arrested in the G1- and S-phase by exposure to the glucocorticoid dexamethasone and nucleotide analogue gemcitabine. At 30% apoptosis, opposite effects were observed on respiratory capacity (71% and 131% of controls, respectively). These changes correlated with alterations in cell size, cytosolic, and mitochondrial marker enzymes. Mitochondrial ATP production and membrane potential were maintained in all treatments, as deduced from high respiratory uncoupling control ratios (UCR). Bcl-2 over-expression did not prevent apoptosis after gemcitabine-treatment, but protected dexamethasone-treated cells from apoptosis, without fully preventing the decline of respiration and cell size. These results, therefore, provide conclusive evidence that alterations in respiratory capacity and enzyme activities per cell are mainly caused by opposite changes in cell size, occurring upon cell cycle arrest triggered by dexamethasone and gemcitabine in the early phase of apoptosis.
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PMID:Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. 1297

At the late stage of etoposide-induced apoptosis in HL-60 cells, marked by condensation of chromatin, mitochondria increase in numbers. There is also a drastic increase in mitochondrial DNA content. This increase in mitochondrial numbers and DNA content is an indicator of mitochondrial proliferation during apoptosis. These proliferating mitochondria exhibit abnormal morphology and are impaired, which is demonstrated by decrease in mitochondrial membrane potential and ATP content. The described apoptosis-induced abnormal mitochondrial proliferation was inhibited by overexpression of Bcl-2 protein, which also diminishes mitochondrial impairment. The increase in mitochondrial DNA levels correlated with elevated expression of one of the regulators of mitochondrial DNA replication, mtSSB. Our data suggest that proliferation of mitochondria may be an integral part of a cascade of apoptotic events.
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PMID:Bcl-2 prevents abnormal mitochondrial proliferation during etoposide-induced apoptosis. 1449 28

Identification of new targets is of utmost importance for the development of efficient apoptosis-modulating drugs. This has become possible from the unraveling of the basic apoptosis mechanisms and notably, from the demonstration of the mitochondrial membrane permeabilization as a central rate-limiting step of numerous models of cell death. Indeed, molecular and pharmacological studies revealed that the adenine nucleotide translocator (ANT) could be a therapeutic target. First, ANT is a bi-functional protein. It mediates the exchange of cytosolic ADP and mitochondrial ATP, and contributes to apoptosis via its capacity to become a lethal pore. Second, both ANT functions are under the control of the (anti)-oncogenes from the Bax/Bcl-2 family, and third, agents as diverse as proteins, lipids, ions, pro-oxidants or chemotherapeutic agents directly modulate the pore-forming activity of ANT. Here, we will review the mode of apoptosis induction by various classes of chemotherapeutic agents, which all influence directly ANT pro-apoptotic function. Hopefully, this will yield several clues to the modulation of apoptosis from a therapeutic perspective.
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PMID:The adenine nucleotide translocator: a new potential chemotherapeutic target. 1453 52

In contrast to the well-established anti-apoptotic effect of Bcl-2 protein, we have recently demonstrated that Bcl-2 overexpression by vaccinia virus causes apoptosis in BSC-40 cells, while it prevents apoptosis in HeLa G cells. Given the key role of mitochondria in the process of apoptosis, we focused on effects of Bcl-2 expression on mitochondrial energetics of these two cell lines. In this study we present data indicating that BSC-40 cells derive their ATP mainly from oxidative phosphorylation whereas HeLa G cells from glycolysis. More importantly, we show that in both cell lines, Bcl-2 inhibits mitochondrial respiration and causes a decrease of the ATP/ADP ratio. However, it appears that BSC-40 cells cannot sustain this decrease and die, while HeLa G cells survive, being adapted to the low ratio of ATP/ADP maintained by glycolysis. Based on this observation, we propose that the outcome of Bcl-2 expression is determined by the type of cellular ATP synthesis, namely that Bcl-2 causes apoptosis in cells relying on oxidative phosphorylation.
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PMID:Inhibitory effects of Bcl-2 on mitochondrial respiration. 1453 29

Selection of tumor cell lines with anticancer drugs has led to the appearance of multidrug-resistant (MDR) subclones with P-glycoprotein 1 (P-gp1) expression. These cells are cross-resistant to several structurally and functionally dissimilar drugs. Interestingly, in the process of gaining resistance, MDR cells become hypersensitive or collaterally sensitive to membrane-active agents, such as calcium channel blockers, steroids, and local anaesthetics. In this report, hypersensitivity to the calcium channel blocker, verapamil, was analyzed in sensitive and resistant CHO cell lines. Our results show that treatment with verapamil preferentially induced apoptosis in MDR cells compared to drug-sensitive cells. This effect was independent of p53 activity and could be inhibited by overexpression of the Bcl-2 gene. The induction of apoptosis by verapamil had a biphasic trend in which maximum cell death occurred at 10 microM, followed by improved cell survival at higher concentrations (50 microM). We correlated this effect to a similar biphasic trend in P-gp1 ATPase activation by verapamil in which low concentrations of verapamil (10 microM) activated ATPase, followed by inhibition at higher concentrations. To confirm the relationship between apoptosis and ATPase activity, we used two inhibitors of P-gp1 ATPase, PSC 833 and ivermectin. These ATPase inhibitors reduced hypersensitivity to verapamil in MDR cells. In addition, low concentrations of verapamil resulted in the production of reactive oxygen species (ROS) in MDR cells. Taken together, these results show that apoptosis was preferentially induced by P-gp1 expressing cells exposed to verapamil, an effect that was mediated by ROS, produced in response the high ATP demand by P-gp1.
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PMID:A mechanism for P-glycoprotein-mediated apoptosis as revealed by verapamil hypersensitivity. 1456 77

We explored whether hypoxic preconditioning minimizes oxidative injury induced by overdistension/emptying in the rat bladder. For hypoxic preconditioning, female Wistar rats were placed in a hypobaric chamber (380 Torr) 15 h day(-1) for 28 days. Overdistension was induced by infusion of two times the threshold volume of saline into the bladder and was maintained for 1 or 2 h, followed by drainage/emptying. During overdistension (ischaemia) and emptying (reperfusion) periods, a bursting increase of reactive oxygen species (ROS) from the bladder was originated from the large numbers of infiltrating leucocytes and scattered resident cells, including urothelial, submucosal, and smooth muscle cells. ROS impaired the voiding function by a reduction of bladder afferent and efferent nerve activity and bethanecol- or ATP-induced detrusor contraction. ROS enhanced pro-apoptotic mechanisms, including increases in the Bax/Bcl-2 ratio, CPP32 expression, and poly(ADP-ribose) polymerase (PARP) fragments with subsequent apoptotic cell formation in the insulted bladders. Hypoxia preconditioning up-regulated Bcl-2 expression in the bladder and significantly reduced the levels of ROS and apoptosis detected in the overdistension/emptying bladders and preserved partial voiding function. Bcl-2 up-regulation by hypoxia preconditioning contributes protection against overdistension/emptying-induced oxidative stress and injury in the bladder.
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PMID:Hypoxia preconditioning attenuates bladder overdistension-induced oxidative injury by up-regulation of Bcl-2 in the rat. 1460 4

The present study tests the hypothesis that a PaCO(2) of 27 mmHg for 1 hr results in increased neuronal nuclear Ca(++)/calmodulin-dependent protein kinase IV (CaM kinase IV) activity, pro-apoptotic protein expression and DNA fragmentation in the cerebral cortex of newborn piglets. Hypocapnic (HC) and normocapnic newborn piglets were studied. Tissue levels of ATP and phosphocreatine (PCr) were lower in the HC group. CaM kinase IV activity and Bax protein density were higher in the HC group. Bcl-2 protein density was the same in both groups, resulting in an increased ratio of Bax/Bcl-2 in the HC group. Density of nuclear DNA fragments was greater in the HC group and varied inversely with ATP and PCr levels. We conclude that hypocapnia (PaCO(2) 27 mmHg) results in increased expression of pro-apoptotic proteins and fragmentation of nuclear DNA in newborn piglets.
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PMID:The effect of hypocapnia (PaCO2 27 mmHg) on CaM kinase IV activity, Bax/Bcl-2 protein expression and DNA fragmentation in the cerebral cortex of newborn piglets. 1462 22

Bid is a proapoptotic Bcl-2 family protein, which on activation translocates to mitochondria and induces damage to the organelles. Activation of Bid depends on its proteolytic processing into truncated forms of tBid. Bid is highly expressed in the kidneys; however, little is known about its role in renal pathophysiology. In this study, we initially examined Bid activation in cultured rat kidney proximal tubular cells following ATP depletion. The cells were depleted of ATP by azide incubation in the absence of metabolic substrates and then returned to normal culture medium for recovery. Typical apoptosis developed during recovery of ATP-depleted cells. This was accompanied by Bid cleavage, releasing tBid of 15 and 13 kDa. Bid cleavage was abolished in cells overexpressing Bcl-2, an antiapoptotic gene. It was also suppressed by caspase inhibitors. Peptide inhibitors of caspase-9 were more effective in blocking Bid cleavage compared with inhibitors of caspase-8 and caspase-3. Provision of glucose, a glycolytic substrate, during azide incubation inhibited Bid cleavage as well, indicating that Bid cleavage was initiated by ATP depletion. Consistently, Bid cleavage was also induced following ATP depletion by hypoxia or mitochondrial uncoupling. Of significance, cleaved Bid translocated to mitochondria, suggesting a role for Bid in the development of mitochondrial defects in ATP-depleted cells. Finally, Bid cleavage was induced during renal ischemia-reperfusion in the rat. Together, these results provide the first evidence for Bid activation in kidney cells following ATP depletion in vitro and renal ischemia in vivo.
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PMID:Bid activation in kidney cells following ATP depletion in vitro and ischemia in vivo. 1467 45

Our previous report has showed that the treatment of 48 h with 22 mM glucose prevents hypoxia-induced cardiac cell death. In the present study, we investigated whether high glucose affects the mitochondrial death pathway during hypoxia, and if it does, what relates to the high glucose induced cardioprotection. Heart-derived H9c2 cells were incubated in low (5.5 mM) or high (22 mM) glucose medium for 48 h, then transferred to a normoxic or hypoxic condition. The hypoxia-induced reduction of mitochondrial redox potential, assessed by MTT assay, was inhibited in high glucose treated cells. The mitochondrial membrane potential was significantly decreased by hypoxia in low glucose treated cells, but not in high glucose treated cells. The hypoxia-induced cytoplasmic accumulation of cytochrome c, released from the mitochondria, was blocked by a treatment of high glucose. High glucose did not induce the expression of an antiapoptotic protein Bcl-2, nor did it reduce a proapoptotic protein Bax, but it did inhibit a hypoxia-induced downregulation of Bcl-2. The cellular ATP contents were not changed by the treatment of high glucose for 48 h, and the hypoxia-induced decline of intracellular ATP level was observed in high glucose treated cells and in low glucose. A glycolytic inhibitor, 2-deoxyglucose, did not reverse the high glucose induced reduction of LDH release. The elevation of [ROS](i) induced by hypoxia was inhibited in high glucose treated cells. These results suggest that high glucose induced cardioprotection may be accounted for in part by the preservation of MMP and the maintenance of a basal level of [ROS](i) during hypoxia.
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PMID:High-glucose induced protective effect against hypoxic injury is associated with maintenance of mitochondrial membrane potential. 1503 43

Olomoucine and Roscovitine are two ATP-competing compounds described as specific inhibitors of cyclin-dependent kinases (CDK). Both drugs showed to induce apoptosis in SH-SY5Y, a neuroblastoma-derived cell line. In these cells, neither Bcl-2 nor Bcl-XL overexpression conferred any resistance to both drugs. However, a partial protective effect was detected when cells were treated with a general inhibitor of caspases (zVADfmk), cycloheximide (CHX), or actinomycin D (DAct). Interestingly, a synergism in cell protection was observed between zVADfmk and macromolecular synthesis inhibitors, thus suggesting different apoptotic pathways in distinct subpopulations of the cell culture. On the other hand, no lethality was found when cells were treated with either PD98059 or UO126. This discarded Erk1/Erk2 inhibition as the cause of apoptosis. Furthermore, SH-SY5Y cells became resistant to either Olomoucine or Roscovitine upon the induction of differentiation. This resistance correlated with the extent of differentiation and, therefore, the number of cells entering a quiescent state. In conclusion, our results seem to support a role for CDK inhibition as the cause of the apoptotic process triggered by Olomoucine and Roscovitine. In addition, we contribute to define a promising profile as anticancer drugs for both compounds, at least in the treatment of neuroblastoma.
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PMID:Cell differentiation, caspase inhibition, and macromolecular synthesis blockage, but not BCL-2 or BCL-XL proteins, protect SH-SY5Y cells from apoptosis triggered by two CDK inhibitory drugs. 1505 86


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