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)

These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1-5 microM AT or melarsoprol for 6 hours suppressed NF-kappa B DNA binding and enhanced of c-Jun kinase (JNK) activity. Arsenic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNF alpha related receptor interacting protein (RIP). In contrast to reported observations in acute promyelocytic leukemia, myeloma cell apoptosis was not associated with either the downregulation of Bcl-2 protein or with alterations in the expression of other Bcl-2 family members, Bax, Bak, Bag, and Bcl-xl. This study first shows that arsenic induces apoptotic signaling in MM through the cleavage of TNF alpha related receptor interacting protein (RIP). RIP is a key downstream protein in FasL/ TNF alpha /TRAIL induced apoptosis and a major antiapoptotic adaptor of pathways through NF-kappa B and JNK. RIP has not been previously characterized in myeloma. This study supports the hypothesis that arsenicals share common mediators (RIP, NF-kappa B, PARP, caspase-3) with death receptor induced apoptosis. These studies provide an important insight into the molecular mechanism of AT induced apoptosis and can be used in the development of adjuvant therapy for MM, presently an incurable disease.
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PMID:RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells. 1531 84

Synthetic oligodeoxynucleotides (CpG-ODNs) and bacterial DNA containing unmethylated CpG dinucleotides in the context of particular base sequences (CpG motifs) are known to inhibit anti-IgM-induced growth arrest and apoptosis of WHEI 231 B lymphocytes, and spontaneous apoptosis of mature spleen B cells in a sequence-specific fashion of the CpG-ODN. Here we report that CpG-ODN protects from the cell death induced by gamma-irradiation of primary mouse spleen cells as well as mouse RAW 264.7 macrophage cells and human RPMI 8226 B cells. Experimental results showed that CpG-ODN promotes growth of the cells, and protects the cells from gamma-irradiation-induced cell death accompanying Bcl-xS/L and Bcl-2 upregulation. Furthermore, survival of macrophages was enhanced when splenocytes were pretreated with CpG-ODN. Our results suggest the potential application of CpG-ODNs for more efficient cancer radiotherapy by enhancing survival of normal immune cells after radiation damage.
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PMID:CpG-oligodeoxynucleotide protects immune cells from gamma-irradiation-induced cell death. 1612 3

Our experiments aimed to clarify the mechanism by which host cell apoptosis is inhibited by infection with the intracellular protozoan parasite, Toxoplasma gondii (T. gondii). Mouse spleen cells were cultured in 6-well plates with RPMI 1640/ 10% FBS at 37?, in a 5% CO2 atmosphere. Apoptosis of spleen cells was induced by actinomycin-D (AD) treatment for 1 h prior to infection with T. gondii. A variety of assays were used to assess the progression of apoptosis: DNA size analysis on agarose gel electrophoresis, flow cytometry with annexin V/PI staining, and analysis of expression levels of Bcl-2 family and NF-kappaB mRNA and proteins by RT-PCR, Western blotting, and EMSA. Additionally, transmission electron microscopy (TEM) was performed to observe changes in cell morphology. Fragmentation of DNA was inhibited in spleen cells treated with AD and T. gondii 5 h and 18 h post infection, respectively, and flow cytometry studies showed a decreased apoptotic rates in AD and T. gondii treated spleen cells. We observed decreased expression of Bax mRNA and protein, while levels of Bcl-2 mRNA remained constant in spleen cells treated with AD and T. gondii. Caspase 3 and PARP were inactivated in cells treated with AD and T. gondii, and increased levels of cleaved caspase 8 were also observed. Analysis of EMSA and Western blot data suggests that activation of transcription factor NF-kappaB may be involved in the blockade of apoptosis by T. gondii. TEM analysis showed nuclear fragmentation and chromatin condensation occurring in spleen cells treated with AD; however, such apoptosis- associated morphological changes were not observed in cells treated with both AD and T. gondii tachyzoites. Together, these data show that T. gondii infection inhibits AD induced apoptosis via caspase inactivation and NF-kappaB activation in mouse spleen cells.
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PMID:Toxoplasma gondii inhibits apoptosis in infected cells by caspase inactivation and NF-kappaB activation. 1719 17

Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind antiapoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the 6 antiapoptotic human Bcl-2 family members, we found that Nur77/TR3 binds strongest to Bcl-B, showing selective reactivity with Bcl-B, Bcl-2, and Bfl-1 but not Bcl-X(L), Mcl-1, or Bcl-W. Nur77 converts the phenotype of Bcl-B from antiapoptotic to proapoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI 8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI 8226 myeloma cells through a Bcl-B-dependent mechanism. Because Bcl-B is abundantly expressed in plasma cells and some myelomas, these findings raise the possibility of exploiting the Nur77/Bcl-B mechanism for apoptosis for eradication of autoimmune plasma cells or myeloma.
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PMID:Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. 1722 26

Agents antagonizing the anti-apoptotic Bcl-2 protein have been shown to restore normal apoptotic processes in cancer cells. Since upregulation of Bcl-2 is often observed in recurrent or refractory hematological malignancies, we were prompted to investigate whether drug-selected leukemia cells overexpressing Bcl-2 were more susceptible to Bcl-2 antagonists. The current study showed that a camptothecin (CPT)-selected human leukemia cell line (CPT-K5) had remarkably higher expression levels of Bcl-2 than its drug sensitive parental cell (RPMI 8402). A small molecule inhibitor of Bcl-2, HA14-1, induced much more extensive apoptosis in CPT-K5 than in RPMI 8402 cells, as characterized by DNA fragmentation, loss of mitochondrial membrane potential (Deltapsi(m)) and plasma membrane integrity, as well as the activation of caspase. Taken together, these findings suggest that small molecule Bcl-2 inhibitors may represent a promising class of alternative agents for the treatment of Bcl-2 overexpressed refractory or recurrent hematological malignancies when conventional chemotherapy fails.
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PMID:Exploitation of drug-induced Bcl-2 overexpression for restoring normal apoptosis function: a promising new approach to the treatment of multidrug resistant cancer. 1734 40

Targeting the ubiquitin-proteasome pathway has emerged as a potent anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma. Multiple myeloma cell survival is highly dependent on Mcl-1 antiapoptotic molecules. In a recent study, proteasome inhibitors induced Mcl-1 accumulation that slowed down their proapoptotic effects. Consequently, we investigated the role of Bcl-2 family members in bortezomib-induced apoptosis. We found that bortezomib induced apoptosis in five of seven human myeloma cell lines (HMCL). Bortezomib-induced apoptosis was associated with Mcl-1 cleavage regardless of Mcl-1L accumulation. Furthermore, RNA interference mediated Mcl-1 decrease and sensitized RPMI-8226 HMCL to bortezomib, highlighting the contribution of Mcl-1 in bortezomib-induced apoptosis. Interestingly, an important induction of Noxa was found in all sensitive HMCL both at protein and mRNA level. Concomitant to Mcl-1 cleavage and Noxa induction, we also found caspase-3, caspase-8, and caspase-9 activation. Under bortezomib treatment, Mcl-1L/Noxa complexes were highly increased, Mcl-1/Bak complexes were disrupted, and there was an accumulation of free Noxa. Finally, we observed a dissociation of Mcl-1/Bim complexes that may be due to a displacement of Bim induced by Noxa. Thus, in myeloma cells, the mechanistic basis for bortezomib sensitivity can be explained mainly by the model in which the sensitizer Noxa can displace Bim, a BH3-only activator, from Mcl-1, thus leading to Bax/Bak activation.
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PMID:Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. 1754 23

Overexpressing antiapoptotic Bcl-2 proteins to suppress apoptosis is one major mechanism via which cancer cells acquire drug resistance against cancer therapy. Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4 H-chromene-3-carboxylate (HA 14-1) is one of the earliest small-molecule antagonists against antiapoptotic Bcl-2 proteins. Since its discovery, HA 14-1 has been shown to be able to synergize a variety of anticancer agents. HA 14-1 also could selectively eliminate tumor cells with elevated level of Bcl-2 protein. HA 14-1, therefore, is being intensely investigated as a potential anticancer agent. Previous reports of HA 14-1 implied that it may not be stable, raising the question of whether HA 14-1 is a suitable drug candidate. The potential stability also raised the concern about whether HA 14-1 is the bioactive species. In this report, we confirm that HA 14-1 is not stable under physiological conditions: it rapidly decomposes in RPMI cell culture medium with a half-life of 15 min. This decomposition process also generates reactive oxygen species (ROS). To identify the actual candidate(s) for the observed bioactivity of HA 14-1, we characterized the structures, quantified the amount, and evaluated the bioactivities of the decomposed products. We also used ROS scavengers to explore the function of ROS. From these studies, we established that none of the decomposition products could account for the bioactivity of HA 14-1. ROS generated during the decomposition process, however, are critical for the in vitro cytotoxicity and the apoptosis induced by HA 14-1. This study demonstrates that HA 14-1 is not stable under physiological conditions and that HA 14-1 can generate ROS through its decomposition, independent of Bcl-2 antagonism. Because of its intrinsic tendency to decompose and to generate ROS, caution should be taken in using HA 14-1 as a qualified antagonist against antiapoptotic Bcl-2 proteins.
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PMID:Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H- chromene-3-carboxylate (HA 14-1), a prototype small-molecule antagonist against antiapoptotic Bcl-2 proteins, decomposes to generate reactive oxygen species that induce apoptosis. 1787 42

Progesterone (P4) is frequently used in the treatment of threatened abortion, prevention of recurrent miscarriage and threatened preterm labor. However, little is known about the molecular mechanism of P4 in the regulation of extravillous trophoblasts' (EVTs) function. This study was designed to examine the presence of progesterone receptor (PR) in the human trophoblast-derived HTR-8/SV neo cell line, which is a possible model of EVTs, and the effects of P4 on apoptosis in those cells. The HTR-8/SV neo cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 microg/ml streptomycin. When the cell the population reached 50% confluency, the cells were stepped down to serum-free conditions in the presence or absence of graded concentrations of P4 (1, 10 and 100 ng/ml) for 48 h. The cultured cells were used for RT-PCR, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) assay, immunocytochemistry and western blot analyses. Immunocytochemistry and western blot analyses revealed that PR was evident in HTR-8/SV neo cells. Compared with untreated cultures, treatment with P4 (10 and 100 ng/ml) resulted in significant decreases in the TUNEL-positive rate, Fas, Fas ligand (Fas-L), caspase-8, caspase-3 and poly (ADP-ribose) polymerase (PARP) expression in HTR-8/SV neo cells, and a significant increase in Bcl-2 expression in those cells. Consistently, Fas mRNA expression in those cells was significantly inhibited by the treatment with 10 ng/ml P4 compared with untreated cultures. This study suggests that PR exists in HTR-8/SV neo cells and that P4 inhibits apoptosis by down-regulating Fas, Fas-L, caspase-8, caspase-3 and PARP expression as well as up-regulating Bcl-2 expression in HTR-8/SV neo cells.
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PMID:The effects of progesterone on apoptosis in the human trophoblast-derived HTR-8/SV neo cells. 1796 76

Apo2 ligand (Apo2L)/TRAIL induces apoptosis of cancer cells that express the specific receptors while sparing normal cells. Because the tumor microenvironment protects myeloma from chemotherapy, we investigated whether hemopoietic stroma induces resistance to Apo2L/TRAIL apoptosis in this disease. Apo2L/TRAIL-induced death was diminished in myeloma cell lines (RPMI 8226, U266, and MM1s) directly adhered to a human immortalized HS5 stroma cell line but not adhered to fibronectin. In a Transwell assay, with myeloma in the upper well and HS5 cells in the lower well, Apo2L/TRAIL apoptosis was reduced when compared with cells exposed to medium in the lower well. Using HS5 and myeloma patients' stroma-conditioned medium, we determined that soluble factor(s) produced by stroma-myeloma interactions are responsible for a reversible Apo2/TRAIL apoptosis resistance. Soluble factor(s) attenuated procaspase-8, procaspase-3, and poly(ADP-ribose) polymerase cleavage and diminished mitochondrial membrane potential changes without affecting Bcl-2 family proteins and/or Apo2L/TRAIL receptors. Soluble factor(s) increased the baseline levels of the anti-apoptotic protein c-FLIP in all cell lines tested. Inhibition of c-FLIP by means of RNA interference increased Apo2/TRAIL sensitivity in RPMI 8226 cells. Unlike direct adhesion to fibronectin, soluble factor(s) have no impact on c-FLIP redistribution within cellular compartments. Cyclohexamide restored Apo2L/TRAIL sensitivity in association with down-regulation of c-FLIP, suggesting that c-FLIP synthesis, not intracellular traffic, is essential for soluble factor(s) to regulate c-FLIP. Additionally, IL-6 conferred resistance to Apo2L/TRAIL-mediated apoptosis in association with increased c-FLIP levels. In conclusion, the immune cytotoxic effect of Apo2L/TRAIL can be restored at least in part by c-FLIP pathway inhibitors.
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PMID:Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP. 1820 50

Small cell lung cancer constitutes 15-20% cases of lung cancers, currently the leading cause of death from malignant diseases. It also causes the demise of >90% of affected individuals in 5 years. We have established a new SCLC cell line STP54 derived from fine needle aspirate of metastatic supraclavicular lymph node of 54 -year-old women for model experiments. The primary tumor was diagnosed by histopathological examination as combined type of small cell lung cancer with a non-small cell component. We cultured the cancer cells in the RPMI 1640 medium. In the long-term culture only the small cell component survived. The cell line was established after 30 passages and then characterized by performing cell morphology, cell growth analysis, tumorigenicity in vitro and flow cytometry analysis of selected markers (like NCAM, cytokeratines, HLA-ABC, Fas, Bcl-2, p53, CXCR4, CD210). The cells were growing in floating aggregates and show features suggesting its invasiveness. We suggest that this new cell line may serve as a valuable tool for further studies on lung tumor biology, molecular pathogenesis and metastatic mechanism.
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PMID:Characterization of a new small cell lung cancer (SCLC) cell line STP54 derived from a metastatic bioptate of a combined type of SCLC with Non-SCLC component. 1941 48


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