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)

Experimental and human data have shown that certain seizures cause damage to brain. Such neuronal loss may result in cognitive impairments and perhaps contribute to the development or phenotype of emergent epilepsy. Recent work using genetically modified mice, Tat protein transduction, and viral vectors has shown functional effects of manipulating Bcl-2 and Bcl-w, heat shock proteins, caspases, and their regulators and endonucleases on neuronal death in models of status epilepticus. Ancillary effects on seizure induction and excitability thresholds have emerged for several genes suggesting additional properties of therapeutic potential. Differing hippocampal expression of certain Bcl-2 family genes, elevated endoplasmic reticulum stress chaperones, and death receptor pathway modulation in epilepsy patients support clinical relevance of this focus. These findings may yield potentially valuable adjunctive neuroprotective or anti-epileptogenic strategies.
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PMID:Modulators of neuronal cell death in epilepsy. 1782 63

Benzene, a well-known human carcinogen, is a commonly used industrial chemical that evokes further toxicological concern because of its potential genotoxic risks as a constituent of petrol and the byproduct of combustion and cigarette smoke. The present study investigated the effects of benzene inhalation on the expression of pro- and antiapoptogenic genes in lung epithelia. Immunohistochemical expression was assessed for antiapoptotic Bcl-2 family proteins, including Bcl-2, Bcl-w, and Bag-1 as well as proapoptotic subfamily members with Bcl-2 homology (BH)1 1-3, namely Bax, those that consist of only the BH3 region, represented by Bad, and proapoptotic gene expression for p53. Rats exposed to benzene via inhalation (300 ppm) for 7 days showed a significant upregulation of proapoptotic gene expression for p53, Bax, and Bad as assessed by a semiquantitative segmental analysis of the lung epithelia, including bronchioles, terminal bronchioles, respiratory bronchioles, and alveoli. Bag-1, an antiapoptogenic gene, was also found to have significant upregulated expression in lung epithelia. Since the underlying mechanisms by which Bag-1 exerts its antiapoptogenic effects are not known, benzene may target the protein chaperones hsc70/hsp70, or RING finger protein associated with Bag-1 activity. Alternatively, the significant downregulation of Bcl-2 may have diminished the antiapoptotic synergism necessary for the effectiveness of Bag-1. Both Bcl-2 and Bcl-w were found to be significantly downregulated compared to the proapoptotic counterparts. These data support the role of benzene in activating proapoptogenic events that lead to the upregulation of gene expression that may provide a crucial defense mechanism within lung parenchyma to reduce mutation hazard and potential carcinogenic effects of benzene-initiated pathogenesis.
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PMID:Differentially expressed pro- and anti-apoptogenic genes in response to benzene exposure: Immunohistochemical localization of p53, Bag, Bad, Bax, Bcl-2, and Bcl-w in lung epithelia. 1809 15

This review focuses on the recent patents and use of small-molecule inhibitors (SMIs) of Bcl-2 family proteins as therapeutic agents against cancer. Bcl-2 members are crucial regulators of apoptotic cell death. Apoptosis is an evolutionarily conserved process of programmed cell death that plays an essential role in organism development and tissue homeostasis. Several mechanisms exist allowing cells to escape programmed cell death among them is the overexpression of the antiapoptotic proteins. Cancer cells are often found to overexpress many of these members such as Bcl-2, Bcl-X(L), Mcl-1, Bcl-w and A1/Bfl1 and are usually resistant to a wide range of anti-cancer drugs and treatments. Many groups have been working to develop anti-cancer drugs that block the function of anti-apoptotic Bcl-2 members, thus favoring cell death. Methods include the downregulation of Bcl-2 expression or the use of peptides or small organic molecules to the Bcl-2 binding pocket, preventing its sequestration of proapoptotic proteins such as Bid and Bim. One of the most promising aspects of SMIs in treating cancer is that their targets and mechanisms of action are different from those of cytotoxic drugs and radiation. This makes it feasible to combine SMIs with other treatments, creating a synergistic therapy, without likely development of cross-resistance or increased toxicity. A broad-spectrum or "pan" SMI which targets multiple Bcl-2 family proteins is the goal.
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PMID:Small-molecule inhibitors of Bcl-2 family proteins as therapeutic agents in cancer. 1828 21

Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens.
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PMID:ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. 1845 Nov 70

Bcl-w belongs to the prosurvival group of the Bcl-2 family, while the glutamate receptor delta2 (Grid2) is an excitatory receptor that is specifically expressed in Purkinje cells, and required for Purkinje cell synapse formation. A recently published result as well as our own findings have shown that Bcl-w can physically interact with an autophagy protein, Beclin1, which in turn has been shown previously to form a protein complex with the intracellular domain of Grid2 and an adaptor protein, nPIST. This suggests that Bcl-w and Grid2 might interact genetically to regulate mitochondria, autophagy, and neuronal function. In this study, we investigated this genetic interaction of Bcl-w and Grid2 through analysis of single and double mutant mice of these two proteins using a combination of histological and behavior tests. It was found that Bcl-w does not control the cell number in mouse brain, but promotes what is likely to be the mitochondrial fission in Purkinje cell dendrites, and is required for synapse formation and motor learning in cerebellum, and that Grid2 has similar phenotypes. Mice carrying the double mutations of these two genes had synergistic effects including extremely long mitochondria in Purkinje cell dendrites, and strongly aberrant Purkinje cell dendrites, spines, and synapses, and severely ataxic behavior. Bcl-w and Grid2 mutations were not found to influence the basal autophagy that is required for Purkinje cell survival, thus resulting in these phenotypes. Our results demonstrate that Bcl-w and Grid2 are two critical proteins acting in distinct pathways to regulate mitochondrial morphogenesis and control Purkinje cell dendrite development and synapse formation. We propose that the mitochondrial fission occurring during neuronal growth might be critically important for dendrite development and synapse formation, and that it can be regulated coordinately by multiple pathways including Bcl-2 and glutamate receptor family members.
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PMID:Mitochondrial morphogenesis, dendrite development, and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2. 1855 Nov 74

Overexpression of antiapoptotic members of the Bcl-2 family is observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying the antiapoptotic influence of these proteins can potentially overcome this resistance, and may complement conventional chemotherapy. ABT-737 is a BH3-only mimetic and potent inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-X(L), and Bcl-w. In vitro, ABT-737 exhibited concentration-dependent cytotoxicity against a broad panel of lymphoma cell lines including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). ABT-737 showed synergism when combined with the proteasome inhibitors bortezomib or carfilzomib in select lymphoma cell lines and induced potent mitochondrial membrane depolarization and apoptosis when combined with either. ABT-737 plus bortezomib also induced significant apoptosis in primary samples of MCL, DLBCL, and chronic lymphocytic leukemia (CLL) but no significant cytotoxic effect was observed in peripheral blood mononuclear cells from healthy donors. In severe combined immunodeficient beige mouse models of MCL, the addition of ABT-737 to bortezomib enhanced efficacy compared with either drug alone and with the control. Collectively, these data suggest that ABT-737 alone or in combination with a proteasome inhibitor represents a novel and potentially important platform for the treatment of B-cell malignancies.
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PMID:The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. 1859 85

miR-122, a hepato-specific microRNA (miRNA), is frequently down-regulated in human hepatocellular carcinoma (HCC). In an effort to identify novel miR-122 targets, we performed an in silico analysis and detected a putative binding site in the 3'-untranslated region (3'-UTR) of Bcl-w, an anti-apoptotic Bcl-2 family member. In the HCC-derived cell lines, Hep3B and HepG2, we confirmed that miR-122 modulates Bcl-w expression by directly targeting binding site within the 3'-UTR. The cellular mRNA and protein levels of Bcl-w were repressed by elevated levels of miR-122, which subsequently led to reduction of cell viability and activation of caspase-3. Thus, Bcl-w is a direct target of miR-122 that functions as an endogenous apoptosis regulator in these HCC-derived cell lines.
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PMID:miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines. 1869 84

A critical regulator of the apoptotic machinery is the Bcl-2 family proteins whose over expression confers a protective effect on malignant cells against death signals of apoptosis. Cancer cells that are resistant to various anti-cancer drugs and treatment regimen are found to over express these Bcl-2 proteins such as Bcl-2, Bcl-X(L), Mcl-1, Bcl-w, and A1/Bfl1. In recent years there has been an exponential growth in the identification as well as synthesis of non-peptidic cell permeable small-molecule inhibitors (SMIs) of protein-protein interaction. The focus of this article is on inhibitors of anti-apoptotic protein Bcl-2. This review summarizes an up to date knowledge of the available SMIs, their mode of action as well as their current status in preclinical as well as clinical development.
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PMID:Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. 1876 26

Despite tremendous advances over the last 15 years in understanding fundamental mechanisms of apoptosis, this has failed to translate into improved cancer therapy for patients. However, there may now be light at the end of this long tunnel. Antiapoptotic Bcl-2 family members may be divided into two subclasses, one comprising Bcl-2, Bcl-X(L) and Bcl-w and the other Mcl-1 and Bcl2A1. Neutralization of both subclasses is required for apoptosis induction. Solution of the structure of antiapoptotic Bcl-2 family proteins has led to the design of novel small molecule inhibitors. Although many such molecules have been synthesized, rigorous verification of their specificity has often been lacking. Further studies have revealed that many putative Bcl-2 inhibitors are not specific and have other cellular targets, resulting in non-mechanism based toxicity. Two notable exceptions are ABT-737 and a related orally active derivative, ABT-263, which bind with high affinity to Bcl-2, Bcl-X(L) and Bcl-w and may prove to be useful tools for mechanistic studies. ABT-263 is in early clinical trials in lymphoid malignancies, small-cell lung cancer and chronic lymphocytic leukemia, and some patients have shown promising results. In in vitro studies, primary cells from patients with various B-cell malignancies are exquisitely sensitive to ABT-737, exhibiting novel morphological features of apoptosis including marked outer mitochondrial membrane rupture.
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PMID:Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. 1880 58

Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x(L), was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models. The addition of systemic therapy with ABT-737 to the immunization of BALB/c mice with tumor antigen peptide-pulsed dendritic cells (DC) resulted in a significant delay in CT26 murine colon carcinoma tumor growth and improvement in survival. However, the addition of ABT-737 to either a vaccine strategy involving priming with TRP-2 melanoma antigen peptide-pulsed DC and boosting with recombinant Listeria monocytogenes expressing the same melanoma antigen, or the adoptive transfer of TCR transgenic cells, did not result in superior antitumor activity against B16 murine melanoma. In vitro studies failed to demonstrate increased cytotoxic lytic activity when testing the combination of ABT-737 with lymphokine activated killer (LAK) cells, or the death receptor agonists Fas, TRAIL-ligand or TNF-alpha against the CT26 and B16 cell lines. In conclusion, the Bcl-2 inhibitor ABT-737 sensitized cancer cells to the antitumor effect of antigen-specific immunotherapy in a vaccine model for the CT26 colon carcinoma in vivo but not in two immunotherapy strategies against B16 melanoma.
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PMID:Immunosensitization with a Bcl-2 small molecule inhibitor. 1880 35


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