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)

Among the new microtubule-targeted agents, the epothilone family of molecules has shown promising anticancer potential, and clinical trials are currently underway for patupilone (epothilone B) in various cancer indications. In this study, we characterized novel aspects of patupilone's cellular action that may underlie its potent cytotoxicity in human neuroblastoma cells. Patupilone induced mitochondrial membrane potential collapse, mitochondrial morphological changes, and cytochrome c release, leading to apoptosis. Within the first 2 h, patupilone increased the generation of reactive oxygen species (ROS; i.e., superoxides and hydrogen peroxide, 33+/-6 and 51+/-3% increase, respectively), specifically from mitochondria. ROS scavengers and mitochondrial DNA depletion [rho(-) cells] significantly protected cells against patupilone cytotoxicity, indicating that ROS generation is a key event in the initial phase of apoptosis. Although the Bim expression level was not modified by patupilone, this proapoptotic protein accumulated in the mitochondrial compartment (2.4-fold increase at IC70) after only a 6-h treatment. In contrast, Bax and Bcl-2 mitochondrial levels were not changed during treatment. It is noteworthy that ROS inhibition prevented Bim relocalization to mitochondria and mitochondrial membrane changes induced by patupilone. Altogether, our data reveal that patupilone-mediated ROS production by mitochondria initiates the intrinsic signaling cascade by inducing Bim accumulation in mitochondria. These results might explain the superior activity of patupilone in tumor cells compared with paclitaxel that is, until now, the clinical reference among microtubule-stabilizing agents. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator and integrator of apoptotic signals triggered by patupilone.
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PMID:Patupilone-induced apoptosis is mediated by mitochondrial reactive oxygen species through Bim relocalization to mitochondria. 1859 21

Erythropoietin (EPO), a haematopoietic growth factor has been reported to display neuroprotective properties in different animal models. In the present study, we investigated the neuroprotective effects of EPO on Abeta(25-35)-induced neuronal toxicity and its potential mechanisms in PC12 cells. Abeta(25-35) significantly reduced cell viability and increased the number of apoptotic-like cells. In addition, increased ROS production and decreased mitochondrial membrane potential were also found after Abeta(25-35) exposure. All of these phenotypes induced by Abeta(25-35) were markedly reversed by EPO. Pretreatment with EPO prior to Abeta(25-35) exposure significantly elevated cell viability, reduced Abeta(25-35)-induced apoptosis, decreased ROS production, and stabilized mitochondrial membrane potential. Furthermore, EPO also attenuated the downstream cascade following ROS, including Bcl-2/Bax, and caspase-3 activation. Our results suggest that EPO holds potential for neuroprotection and therefore, may be promising for the treatment of Alzheimer's disease.
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PMID:Protective effect of erythropoietin on beta-amyloid-induced PC12 cell death through antioxidant mechanisms. 1863 46

Enhancement of radiation response is possible to be achieved by combination treatment with therapeutic drugs. Previously we have shown that As2O3 in combination with ionizing radiation enhanced radiation response in cervical cancer cells. In this study, we further investigated molecular mechanism of synergistic enhancement of radiation response in combination with As2O3. The combination treatment of HeLa cells induced translocation of Bax to the mitochondria and a marked phosphorylation of Bcl-2. p38 MAPK and JNK were also found to be activated in response to the combination treatment. Pretreatment of PD169316, a p38 MAPK specific inhibitor, completely attenuated the combination treatment-induced mitochondrial relocalization of Bax, and altered Bcl-2 phosphorylation. Moreover, pretreatment of SP600125, JNK specific inhibitor, clearly attenuated Bcl-2 phosphorylation, but did not affect Bax translocation to the mitochondria. In addition, N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant, completely blocked p38 MAPK and JNK activations, Bax relocalization and Bcl-2 phosphorylation. These results indicate that activation of p38 MAPK is specifically required for translocation of Bax to the mitochondria, and both JNK and p38 MAPK are involved in phosphorylation of Bcl-2 in response to combination treatment with gamma-radiation and As2O3, and that ROS is a critical regulator of p38 MAPK and JNK activations. The molecular mechanism elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to radiation treatment.
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PMID:Role of p38 MAPK and JNK in enhanced cervical cancer cell killing by the combination of arsenic trioxide and ionizing radiation. 1869 17

This study is to examine the effects of equol on the H(2)O(2)-induced death of bovine aortic endothelial cells (bAECs) and the mechanism of its protective effects. MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] assay showed that in the control group, cell survival rate decreased significantly, each in proportion to the duration of the H(2)O(2) stimulation (P<0.05), but, in the equol-pretreated group, such decrease was not statistically significant. After Hoechst 33342 staining, in the equol-pretreated group the number of cells with apoptotic morphology decreased significantly. Equol pretreatment effectively inhibited the H(2)O(2)-induced cell death by the reduction of intracellular ROS production (P<0.05). Incubation of bAECs with equol increased the expression of phospho-p38 MAPK and Bcl-2 after the H(2)O(2) exposure compared with their expression without the equol pretreatment. Furthermore, SB203580 inhibited phospho-p38 MAPK expression and increased apoptotic cell death. This study proves equol has a significant antioxidant effect on the bAECs that were exposed to H(2)O(2).
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PMID:Antioxidant effects of equol on bovine aortic endothelial cells. 1870 29

The role of selenium as potential cancer chemopreventive and chemotherapeutic agents has been supported by epidemiological, preclinical and clinical studies. Although cell apoptosis has been evidenced as a critical mechanism mediating the anticancer activity of selenium, the underlying molecular mechanisms remain elusive. In the present study, we showed that selenocystine (SeC), a naturally occurring selenoamino acid, induced caspase-independent apoptosis in MCF-7 breast carcinoma cells, which was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage, caspase activation, DNA fragmentation, phosphatidylserine exposure and nuclear condensation. Moreover, SeC induced the loss of mitochondrial membrane potential (DeltaPsi(m)) by regulating the expression and phosphorylation of Bcl-2 family members. Loss of DeltaPsi(m) led to the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF) which subsequently translocated into the nucleus and induced chromatin condensation and DNA fragmentation. MCF-7 cells exposed to SeC shown increase in total p53 and phosphorylated p53 on serine residues of Ser15, Ser20, and Ser392 prior to mitochondrial dysfunction. Silencing and attenuating of p53 activation with RNA interference and pifithrin-alpha treatment, respectively, partially suppressed SeC-induced cell apoptosis. Furthermore, generation of reactive oxygen species and subsequent induction of DNA strand breaks were found to be upstream cellular events induced by SeC. The thiol-reducing antioxidants, N-acetylcysteine and glutathione, completely blocked the occurrence of cell apoptosis. Taken together, these results suggest that SeC, as a promising anticancer selenocompound, induces MCF-7 cell apoptosis by activating ROS-mediated mitochondrial pathway and p53 phosphorylation.
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PMID:Selenocystine induces caspase-independent apoptosis in MCF-7 human breast carcinoma cells with involvement of p53 phosphorylation and reactive oxygen species generation. 1871 51

The pineal gland hormone melatonin has been recently described to downregulate the intrinsic (or damage-induced) pathway of apoptosis in human leukocytes. These properties appear to depend on a specific mitochondrial signaling of melatonin which is associated with a lower generation of reactive oxygen species and a better control of redox-sensitive components such as the antiapoptotic protein Bcl-2. Other elements upstream in this signaling are expected to contribute regulatory roles that remain unexplored. The aim of this study was to investigate whether the extracellular signal-regulated kinase (ERK), which controls the balance between survival and death-promoting genes throughout the MAPK pathway, is involved in the antiapoptotic signaling of melatonin. Human monocytic U937 cells irradiated with UVB light were used as a model of stress-induced apoptosis. In this model we found that pharmacological concentrations of melatonin (1 mM) were able to decrease superoxide anion production, mitochondrial damage, and caspase-dependent apoptosis by improved Bcl-2 levels and decreased Cyt c release in the cytoplasm. Moreover, melatonin increased the phosphorylative activation of ERK 1/2 independently from the presence of UVB stress, and decreased the UVB-mediated activation of the stress kinases p38 MAPK and JNK. The ERK 1/2 inhibitor PD98059, but not the p38 MAPK inhibitor SB203580, abolished to different extents the effects that melatonin had on the UVB-induced ROS generation, mitochondrial dysfunction, and apoptosis. Using these inhibitors, a cross-talk effect between stress and survival-promoting kinases was tentatively identified, and confirmed the hierarchical role of ERK MAPK phosphorylation in the signaling of melatonin. In conclusion, melatonin sustains the activation of the survival-promoting pathway ERK MAPK which is required to antagonize UVB-induced apoptosis of U937 cells. This kinase mediates also the antioxidant and mitochondrial protection effects of this hormonal substance that may find therapeutic applications in inflammatory and immune diseases associated with leukocyte oxidative stress and accelerated apoptosis.
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PMID:ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells. 1893 Aug 12

Exposure to various toxicants is known to cause apoptosis in various cell types. The spermatogenic cells are particularly sensitive to various deleterious conditions including toxicant exposure. The affected cells might undergo apoptosis; however, the mechanisms may be different for different kinds of insults to the cells. In the present study, we looked into the mechanisms involved in apoptosis after exposure of testicular cells from mice to two different chemicals, diethyl maleate (DEM) and tert-butyl hydroperoxide (TBHP). For the study, cells were maintained for 4 h under various treatments: control (media only), 0.25 mM DEM, 0.5 mM DEM, 0.25 mM TBHP, and 0.5 mM TBHP. The treated cells were then harvested for various estimations, viz. viability, reduced and oxidized glutathione, redox ratio, free radical generation, and ethidium bromide/acridine orange co-staining. mRNA was extracted for RT-PCR analysis of Caspase 3, Caspase 8, Caspase 9, p53, p21, Bax, and Bcl-2. It was observed that both the treatments resulted in decreased levels of reduced glutathione and a concomitant increase in the oxidized form and ROS levels in a dose-dependent manner. The apoptotic cell death was evident from ethidium bromide/acridine orange staining. The mRNA expression pattern of various Caspases showed progressive increase in Caspase 3 and Caspase 9 mRNA in both the treatments in a dose-dependent manner, whereas there was no change in Caspase 8 mRNA expression. p53, p21, and Bax also showed increased expression, whereas Bcl-2 expression remained unchanged in DEM treatments and increased significantly in both TBHP treatments. Hence, the present study indicates the involvement and activation of various apoptotic factors, particularly Caspase 3 and 9 along with p53, in response to exposure of testicular cells to DEM and TBHP.
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PMID:Regulation of apoptosis by Caspases under oxidative stress conditions in mice testicular cells: in vitro molecular mechanism. 1897 86

Polygonatum cyrtonema lectin (PCL), a mannose-binding lectin, has been reported to induce cytotoxicity and apoptosis. Herein, we demonstrated that PCL-induced apoptosis and autophagy in A375 cells. The apoptotic mechanism was that PCL treatment regulated Bax, Bcl-xL and Bcl-2 proteins, leading to mitochondrial depolarization, cytochrome c release and caspase activation. Subsequently, we found that PCL treatment abrogated glutathione antioxidant system and induced mitochondria to generate ROS accumulation, resulting in p38-p53 activation. Moreover, we confirmed that the ROS-p38-p53 pathway was involved in PCL-induced autophagy. In conclusion, these results indicate that PCL induces apoptosis and autophagy via a mitochondrial-mediated ROS-p38-p53 pathway.
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PMID:Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. 1901 May 91

In the human acute myeloid leukemia cell line M07e, the growth factor interleukin-3 (IL-3) induces ROS formation, positively affecting Glut1-mediated glucose uptake and cell survival. The effect of IL-3 and exogenous hydrogen peroxide on cell viability seems to be mediated through inhibition of the cell death commitment, as shown by apoptotic markers such as caspase activities, apoptotic nuclei, and changes in the amount of proteins belonging to the Bcl-2 family. The pivotal role of ROS is confirmed using various antioxidants, such as EUK-134, ebselen, TEMPO, and hydroxylamine probe. In fact, these antioxidants, acting through different mechanisms, decrease glucose transport activity and cell proliferation activated by IL-3 or by low concentrations of hydrogen peroxide. Moreover, antioxidants foster programmed cell death commitment, as shown by the cited apoptotic parameters. EUK-134, a combined superoxide dismutase/catalase mimetic, opposes the effects of IL-3 and H(2)O(2), decreasing phosphorylation levels of signaling enzymes such as Akt, Src tyrosine kinase, and ERK. Results show that ROS production induced by IL-3 can protect leukemic cells from apoptosis, the effect being counteracted by antioxidants. This mechanism may play an important role in supporting acute myeloid leukemia treatment, thus representing a novel therapeutic strategy.
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PMID:Induction of apoptosis in a human leukemic cell line via reactive oxygen species modulation by antioxidants. 1901 34

The mechanisms of apoptosis induced by diallyl disulfide (DADS) were explored in human cervical cancer Ca Ski cells. Flow cytometric analysis, DNA gel electrophoresis and DAPI staining demonstrated that DADS induced apoptosis in Ca Ski cells. DADS induced apoptosis through the production of reactive oxygen species and Ca2+, and induced abrogation of mitochondrial membrane potential (Deltapsim) and cleavage of Bid protein (t-Bid). DADS increased the levels of p53, p21 and Bax, but caused a decrease in the level of Bcl-2. DADS also promoted the activities of caspase-3 leading to DNA fragmentation, thus indicating that DADS-induced apoptosis is caspase-3 dependent. In addition, DADS induced an increase in the level of cytochrome c in the cytoplasm, which was released from mitochondria. BAPTA attenuated the Deltapsim abrogation and significantly diminished the occurrence of DADS-induced apoptosis in Ca Ski cells. In conclusion, DADS-induced apoptosis occurs via production of ROS and caspase-3 and a mitochondria-dependent pathway in Ca Ski cells.
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PMID:Diallyl disulfide (DADS) induces apoptosis in human cervical cancer Ca Ski cells via reactive oxygen species and Ca2+-dependent mitochondria-dependent pathway. 1903 12


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