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)

It is well-established that peptide epitopes derived from human tumor-associated Ags can be recognized by CTL in the context of the MHC molecule. However, the vast majority of Ags described are not vital for survival and growth of the tumor cells, and immunoselection of Ag-loss variants during immunotherapy has been demonstrated in several cases. Malfunctions in death pathways observed in human cancers are often due to overexpression of antiapoptotic proteins in the Bcl-2 protein family, i.e., Bcl-2, Mcl-1, and Bcl-xL. These antiapoptotic proteins are implicated in cancer development, tumor progression, and drug resistance. The general overexpression of the antiapoptotic members of the Bcl-2 family in cancer and the fact that down-regulation or loss of expression of these proteins as a means of immune escape would impair sustained tumor growth makes them very attractive targets for anticancer immunotherapy. Recently, we identified spontaneous T cell responses against Bcl-2- and Mcl-1-derived peptides in patients suffering from cancers of different origin. In this study, we demonstrate that Bcl-xL is a target for T cell recognition in cancer patients. Thus, we describe spontaneous HLA-A2-restricted cytotoxic T cell responses against peptide epitopes derived from Bcl-xL by means of ELISPOT and flow cytometry stainings, whereas no responses were detected against any of the Bcl-xL epitopes in any healthy controls. Moreover, Bcl-xL-specific T cells are cytotoxic against HLA-matched cancer cells of different origin. Thus, cellular immune responses against apoptosis inhibitors like the Bcl-2 family proteins appear to represent a general feature in cancer.
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PMID:Spontaneous immunity against Bcl-xL in cancer patients. 1608 48

Prevention, improved screening, and better treatment regimens have improved cancer incidence and mortality in the last decade. Chemoradiation continues to cause high morbidity in patients undergoing treatment. DNA therapeutics have the potential to modify the genes that cause tumor progression in order to produce a response that is tumor-specific, efficacious and systemic without toxicity to normal cells. The most widely used and most experimentally advanced DNA therapeutic is the antisense oligonucleotide. These oligomers are predominantly used to inhibit mRNA expression. For cancer chemotherapy, the Bcl-2 antisense oligonucleotide is currently in phase III clinical trials. Transcription factor decoys form DNA:protein heteroduplexes and produce cellular responses at the genomic rather than transcriptional level. The use of other transcription factor decoys as oncologic reagents is now being developed. The phenomenon of RNA interference has only recently been discovered to occur in plants as a response to viral infection. Small interfering RNAs cause mRNA inhibition. siRNAs also inhibit expression of mRNA, however the intracellular cascade is quite different. siRNA could prove to be more powerful and longer lasting than antisense. Several DNA therapeutics are currently being studied. This review will focus on antisense oligonucleotides, transcription factor decoys and siRNA with an emphasis on how they can be employed as anticancer agents. Mechanism of action and design strategies will be summarized, as well as therapeutic targets and demonstrated clinical efficacy for each reagent.
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PMID:Oligonucleotides as anticancer agents: from the benchside to the clinic and beyond. 1610 40

While significant advances in the treatment of cancer occured during the last half of the twentieth century, parallel decreases in overall cancer death rates were not observed. Cancer therapy remains an area of significant unmet medical need. Abbott's oncology research programs are focused on pioneering trageted, less toxic therapies, aimed at different aspects of tumor growth and development. Oncology drugs in development at Abbott target several mechanisms of cancer progression by interfering with multiple processes necessary for tumor growth: recruitment of a blood supply, cell proliferation, and the development of metastases. They include a selective endothelin A-receptor antagonist (atrasentan/Xinlay), 3 angiogenesis inhibitors (ABT 510, a thrombospondin mimetic: ABT-869, a multitargeted receptor tyrosine kinase inhibitor; and ABT 828, recombinant human plasminogen kringle 5), a cell proliferation inhibitor (ABT-751, an antimitotic agent), an apoptosis inducer (ABT 737, a Bcl-2 family inhibitor), and a poly(ADP-ribose)polymerase inhibitor.
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PMID:Targeting the unmet medical need: the Abbott Laboratories oncology approach. 1622 44

Over the past 20 years, research on hormonal treatments for prostate cancer focused on maximizing androgen ablation through combination therapy. Unfortunately, maximal androgen ablation increases treatment-related side effects and expense and has not significantly prolonged time to androgen-independent (AI) progression. Intermittent androgen suppression (IAS) is based on the hypothesis that if tumor cells surviving androgen withdrawal can be forced along a normal pathway of differentiation by androgen replacement, then apoptotic potential might be restored, androgen dependence may be prolonged and progression to androgen independence may be delayed. Observations from animal model studies suggest that progression to androgen independence is delayed by IAS and this strategy is now being evaluated in phase III trials. Another strategy for improving therapies in advanced prostate cancer involves targeting genes that are activated by either androgen withdrawal or chemotherapy to delay or prevent the emergence of the resistant AI phenotype. Targeted inhibition of stress-associated increases in gene expression precipitated by androgen withdrawal or chemotherapy may enhance treatment-induced apoptosis and delay progression to AI disease. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, clusterin, Hsp27, and IGFBP-2 and IGFBP-5. The purpose of this paper is to review the rationale and progress in using targeted gene therapies to enhance tumor cell death after androgen withdrawal or taxane chemotherapy. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those not amenable to small molecule or antibody inhibition. The current status and future direction of several antisense oligonucleotides that have potential clinical use in cancer are also reviewed.
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PMID:Beyond simple castration: targeting the molecular basis of treatment resistance in advanced prostate cancer. 1627 54

Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well, although levels of Bax, Bad, or Bak were not altered after treatment with this bispecific antisense oligonucleotide. Indirect down-regulation of inhibitor of apoptosis (IAP) family, including XIAP, cIAP-1 and cIAP-2, via second mitochondria-derived activator of caspases was also observed after bispecific antisense oligonucleotide treatment. Executioner caspase-3, caspase-6, and caspase-7 were shown to be involved in apoptosis induced by bispecific antisense oligonucleotide. This Bcl-2/Bcl-xL bispecific antisense oligonucleotide also enhanced paclitaxel chemosensitivity in PC3 cells, reducing the IC50 of paclitaxel by >90%. These findings illustrate that combined suppression of antiapoptotic Bcl-2 family members using this antisense oligonucleotide could be an attractive strategy for inhibiting cancer progression through alteration of the apoptotic rheostat in androgen-independent prostate cancer.
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PMID:A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells. 1627 90

Myc is a key regulatory protein in higher eukaryotes controlling important cellular functions such as proliferation, differentiation, and apoptosis. Myc is profoundly involved in the genesis of many human and animal cancers, and the abrogation of Myc-induced apoptosis is a critical event in cancer progression. Because the mechanisms that mediate Myc-induced apoptosis are largely unknown, we analyzed protein expression during Myc-induced apoptosis using an isotope-coded affinity tag quantitative proteomics approach and identified that a proapoptotic mitochondrial chloride ion channel, mtCLIC/CLIC4, is induced by Myc. Myc binds to the mtCLIC gene promoter and activates its transcription. Suppression of mtCLIC expression by RNA interference inhibited Myc-induced apoptosis in response to different stress conditions and abolished the cooperative induction of apoptosis by Myc and Bax. We also found that Myc reduces the expression of Bcl-2 and Bcl-xL and that the apoptosis-inducing stimuli up-regulate Bax expression. These results suggest that up-regulation of mtCLIC, together with a reduction in Bcl-2 and Bcl-xL, sensitizes Myc-expressing cells to the proapoptotic action of Bax.
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PMID:Quantitative proteomic analysis of myc-induced apoptosis: a direct role for Myc induction of the mitochondrial chloride ion channel, mtCLIC/CLIC4. 1631 93

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-kappaB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-kappaB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.
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PMID:Role of the unfolded protein response in cell death. 1637 48

The status and interrelationship of p53 family members are critical elements in tumor progression. An intriguing paper in this issue of Cancer Cell (Rocco et al., 2006) reveals a new twist in the interactions between p63 and p73 following DNA damage, underscoring a role for p73 in the proapoptotic regulation of Puma, Noxa, and Bcl-2 in head and neck squamous cell carcinomas (HNSCC). These data define a pathway in which deltaNp63alpha promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program, suggesting that p63 levels and p73 status may be key determinants of tumor response in patients with HNSCC.
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PMID:p63 and p73: teammates or adversaries? 1641 71

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiological pathways that support tumor development while minimizing normal tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The authors will focus on natural health products (NHPs) that have a high degree of antiangiogenic activity but also describe some of their many other interactions that can inhibit tumor progression and reduce the risk of metastasis. NHPs target various molecular pathways besides angiogenesis, including epidermal growth factor receptor (EGFR), the HER-2/neu gene, the cyclooxygenase-2 enzyme, the NF-kB transcription factor, the protein kinases, Bcl-2 protein, and coagulation pathways. The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are confirming the knowledge that is already documented in traditional texts. The following herbs are traditionally used for anticancer treatment and are antiangiogenic through multiple interdependent processes that include effects on gene expression, signal processing, and enzyme activities: Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (turmeric), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinale (ginger), Panax ginseng, Rabdosia rubescens (rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking on clinical trials. More data are required on dose response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as biological response modifiers and adaptogens, potentially enhancing the efficacy of the so-called conventional therapies. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials might be preferred, smaller studies with appropriate end points and surrogate markers for antiangiogenic response could help prioritize agents for the larger resource-intensive phase 3 trials.
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PMID:Targeting angiogenesis with integrative cancer therapies. 1648 11

HAMLET (Human alpha-lactalbumin Made Lethal to Tumor cells) triggers selective tumor cell death in vitro and limits tumor progression in vivo. Dying cells show features of apoptosis but it is not clear if the apoptotic response explains tumor cell death. This study examined the contribution of apoptosis to cell death in response to HAMLET. Apoptotic changes like caspase activation, phosphatidyl serine externalization, chromatin condensation were detected in HAMLET-treated tumor cells, but caspase inhibition or Bcl-2 over-expression did not prolong cell survival and the caspase response was Bcl-2 independent. HAMLET translocates to the nuclei and binds directly to chromatin, but the death response was unrelated to the p53 status of the tumor cells. p53 deletions or gain of function mutations did not influence the HAMLET sensitivity of tumor cells. Chromatin condensation was partly caspase dependent, but apoptosis-like marginalization of chromatin was also observed. The results show that tumor cell death in response to HAMLET is independent of caspases, p53 and Bcl-2 even though HAMLET activates an apoptotic response. The use of other cell death pathways allows HAMLET to successfully circumvent fundamental anti-apoptotic strategies that are present in many tumor cells.
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PMID:HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53. 1650 60


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