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)

Tumour progression is regulated by the balance of proliferation and apoptosis in the tumour cell population. To date, the role of vascular endothelial growth factor (VEGF) in tumour growth has been attributed to the induction of angiogenesis. VEGF has been shown to be a survival factor for endothelial cells, preventing apoptosis by inducing Bcl-2 expression. In both murine (4T1) and human (MDA-MB-231) metastatic mammary carcinoma cell lines, we found that VEGF upregulated Bcl-2 expression and anti-VEGF antibodies reduced Bcl-2 expression. These alterations in Bcl-2 expression were reflected by the levels of tumour cell apoptosis. VEGF resulted in reduced tumour cell apoptosis, whereas its inhibition with anti-VEGF neutralizing antibodies induced apoptosis directly in tumour cells. Therefore, in addition to its role in angiogenesis and vessel permeability, VEGF acts as a survival factor for tumour cells, inducing Bcl-2 expression and inhibiting tumour cell apoptosis.
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PMID:Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. 1146 Oct 89

This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.
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PMID:Rational approaches to design of therapeutics targeting molecular markers. 1172 98

One of the major challenges of early-stage breast cancer is to select the adjuvant therapy that ensures the most benefits and the least harm for the patient. The definition of accurate predictive factors is therefore of paramount importance. So far the choice of adjuvant therapy has been based on the number of affected lymph nodes and the hormone receptor status of the patient. This paper evaluates the use of other tumor-related markers as predictive factors for adjuvant therapy. These include HER2, p53 and Bcl-2, cathepsin B, p27, proliferating cell nuclear antigen (PCNA), cyclin D, Ki-67, and vascular endothelial growth factor (VEGF).
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PMID:Predictive factor for the response to adjuvant therapy with emphasis in breast cancer. 1173 86

Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4(+) leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.
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PMID:Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. 1187 95

Similar to endothelial cells (ECs), vascular endothelial growth factor (VEGF) induces Bcl-2 expression on VEGF receptor-positive (VEGFR(+)) primary leukemias and cell lines, promoting survival. We investigated the molecular pathways activated by VEGF on such leukemias, by performing a gene expression analysis of VEGF-treated and untreated HL-60 leukemic cells. One gene to increase after VEGF stimulation was heat shock protein 90 (Hsp90). This was subsequently confirmed at the protein level, on primary leukemias and leukemic cell lines. VEGF increased the expression of Hsp90 by interacting with KDR and activating the mitogen-activated protein kinase cascade. In turn, Hsp90 modulated Bcl-2 expression, as shown by a complete blockage of VEGF-induced Bcl-2 expression and binding to Hsp90 by the Hsp90-specific inhibitor geldanamycin (GA). GA also blocked the VEGF-induced Hsp90 binding to APAF-1 on leukemic cells, a mechanism shown to inhibit apoptosis. Notably, VEGF blocked the proapoptotic effects of GA, correlating with its effects at the molecular level. Earlier, we showed that in some leukemias, a VEGF/KDR autocrine loop is essential for cell survival, whereas here we identified the molecular correlates for such an effect. We also demonstrate that the generation of a VEGF/VEGFR autocrine loop on VEGFR(+) cells such as ECs, also protected them from apoptosis. Infection of ECs with adenovirus-expressing VEGF resulted in elevated Hsp90 levels, increased Bcl-2 expression, and resistance to serum-free or GA-induced apoptosis. In summary, we demonstrate that Hsp90 mediates antiapoptotic and survival-promoting effects of VEGF, which may contribute to the survival advantage of VEGFR(+) cells such as subsets of leukemias.
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PMID:VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. 1189 90

Acute cerebral ischemia causes hypoxic neuronal cell death by necrosis and apoptosis. Expression of anti-apoptotic transgenes in ischemic brain may provide a useful therapeutic strategy for alleviation of postischemic damage. The present study investigates liposome-mediated transfer of the human bcl-2 protein in a rat model of focal transient ischemia due to middle cerebral artery (MCA) occlusion. Two different types of plasmid vectors were used for bcl-2 expression: one driven by the constitutive cytomegalovirus promoter (pCMV) and another based on the hypoxia-inducible human vascular endothelial growth factor promoter (pHRE). Cationic liposome/plasmid DNA complexes (lipoplexes) were injected directly into the cerebrospinal fluid (CSF) of rats immediately after MCA occlusion. The brains of treated and control animals were analyzed 48 h later. Infarct volumes and numbers of apoptotic cells were quantified. Occlusion of the MCA resulted in ipsilateral cerebral infarcts in all study animals. Transfer of the bcl-2 gene resulted in high level widespread protein expression in the case of the pCMV-bcl2 plasmid, while animals treated with the pHRE-bcl2 vector showed lower expression levels of bcl2 which were in addition limited to the ischemic area. Treatment with pCMV-bcl2, but not with pHRE-bcl2, was able to significantly reduce the infarct volume, which was 109 +/- 8 mm(3) for pCMV-bcl2, 152 +/- 29 mm(3) for pHRE-bcl2, and 155 +/- 18 mm(3) for control animals. Animals transfected with either vector showed a significant reduction in numbers of apoptotic cells in the infarct and penumbra area compared with controls. There were no short-term neurological side-effects of the CSF injection of lipoplexes or of bcl-2 expression. In conclusion, the hypoxia-inducible bcl-2 expression mediated by intrathecal lipoplexes may represent a novel, biologically safe and lesion-selective therapeutic approach for neuroprotection after acute cerebral ischemia. DOI: 10.1038/sj/gt/3301676
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PMID:Liposome-mediated transfer of the bcl-2 gene results in neuroprotection after in vivo transient focal cerebral ischemia in an animal model. 1196 Mar 18

This study examined the potential role of angiotensin type 2 (AT(2)) receptor on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by femoral artery ligature in both wild-type and AT(2) gene-deleted mice (Agtr2(-)/Y). After 28 days, angiogenesis was quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. Protein levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), Bax, and Bcl-2 were determined by Western blot analysis in hindlimbs. The AT(2) mRNA level (assessed by semiquantitative RT-PCR) was increased in the ischemic hindlimb of wild-type mice. Angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio, 1.9- and 1.7-fold, respectively, in Agtr2(-)/Y mice compared with controls. In ischemic leg of Agtr2(-)/Y mice, revascularization was associated with an increase in the antiapoptotic protein content, Bcl-2 (211% of basal), and a decrease (60% of basal) in the number of cell death, determined by TUNEL method. Angiotensin II treatment (0.3 mg/kg per day) raised angiogenic score, blood perfusion, and both VEGF and eNOS protein content in ischemic leg of wild-type control but did not modulate the enhanced angiogenic response observed in untreated Agtr2(-)/Y mice. Finally, immunohistochemistry analysis revealed that VEGF was mainly localized to myocyte, whereas eNOS-positive staining was mainly observed in the capillary of ischemic leg of both wild-type and AT(2)-deficient mice. This study demonstrates for the first time that the AT(2) receptor subtype may negatively modulate ischemia-induced angiogenesis through an activation of the apoptotic process.
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PMID:Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. 1203 96

Taxane-based therapies appear to have a significant efficacy in clinical trials on hormone-refractory prostate carcinoma. In the present study, we investigated the cellular response of androgen-independent prostate carcinoma cell lines to the novel taxane IDN 5109 (BAY 59-8862) and evaluated its antitumor activity. In previous preclinical studies, this new paclitaxel (PTX) analogue was characterized by high tolerability and antitumor efficacy, ability to overcome multidrug resistance, and activity by oral administration. Upon treatment, DU145 and PC3 prostate carcinoma cell lines underwent a transient mitotic arrest. This was followed by G1 arrest and rapid occurrence of apoptosis in DU145 cells, whereas in PC3 cells, which are defective for the postmitotic checkpoint, a slow cell death was preceded by DNA endoreduplication. At the biochemical level, such events were associated with tubulin polymerization, activation of the mitosis-promoting factor, and phosphorylation of Bcl-X(L)/Bcl-2/Raf-1. In addition, IDN 5109 shared with PTX the ability to down-regulate the expression of the two potent angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. These findings indicated that IDN 5109 affected the same pathways involved in the cellular response to PTX and suggested that an antiangiogenic effect mediated by inhibition of paracrine stimulation of endothelial cells might contribute to the antitumor effect of both drugs. In in vivo experiments, the new taxane displayed a superior and more persistent effect compared with PTX against DU145 tumor xenografts. Such an effect was associated with pronounced reduction of the tumor microvessel density, superior to that achieved by PTX. These results support a potential therapeutic advantage of IDN 5109 over PTX against hormone-refractory prostate carcinoma.
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PMID:Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer. 1217 97

Hepatocellular carcinoma (HCC) is one of the most common reasons for malignancy-related death in Africa and Asia and is still recognised as the leading cancer in men in Taiwan. Despite enthusiastic efforts in early diagnosis, aggressive surgical treatment and application of additional nonoperative modalities, its prognosis is still dismal. This emphasises the necessity to develop new measures and strategies for its prevention. Inducible cyclooxygenease 2 (COX-2) is an immediate-early (IE) response gene and extensive studies conducted over the past few years have recognised its overexpression in several carcinomas and thus its implication in carcinogenesis. Recent studies have suggested that overexpression of COX-2 might be one of the leading factors in hepatic carcinogenesis. COX-2 can induce angiogenesis via vascular endothelial growth factor (VEGF) and prostaglandin production and can also inhibit apoptosis by inducing the antiapoptotic factor Bcl-2 as well as activating antiapoptotic signalling through Akt/PKB. Therefore, the use of selective inhibitors for the downregulation of COX-2 activity might be a target for preventing hepatic carcinoma development.
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PMID:COX-2 - a target for preventing hepatic carcinoma? 1222 62

The call for the discovery of less toxic, more selective, and more effective agents to treat cancer has become more urgent. Inhibition of angiogenesis continues to be one of the main streams in the current cancer drug discovery activity. Insights into tumor angiogenesis biology have led to the identification of a number of molecules, which are important for the progression of these processes. Of particular interest is a group of growth factors including fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor. These growth factors and their corresponding receptor tyrosine kinases have become important targets for inhibition of the proliferation of endothelial cells, the main component of blood vessels. The validated targets for inhibition of angiogenesis also include a family of matrix metalloproteinases and cell adhesion molecules. In the closely related area, protein kinases have emerged as one of the most important targets for drug discovery. Besides growth factor receptor tyrosine kinases, numerous other protein kinases implicated in malignancies have been identified including non-receptor kinases such as Bcl-Abl and Src kinases. In addition, the cell cycle regulators (cyclin-dependent kinases, p21 gene) and apoptosis modulators (Bcl-2 oncoprotein, p53 tumor suppressor gene, survivin protein, etc) have also attracted renewed interest as potential targets for anticancer drug discovery. Other molecular targets include protein farnesyltransferase (FTase), histone deacetylase (HDAC), and telomerase, which have essential roles in cellular signal transduction pathways (FTase, HDAC) and cell life-span (telomerase). This review presents a comprehensive summary and discussion on the most important targets currently attracting a great deal of interest in contemporary anticancer drug design and discovery. Recent advances complementing these targets are also highlighted.
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PMID:Current targets for anticancer drug discovery. 1255 68


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