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)

The last decade has witnessed the introduction of a large number of novel, molecularly targeted agents into the therapeutic armamentarium against diverse forms of cancer, including leukemia. Such agents include signal transduction, cell cycle, histone deacetylase, Hsp90, proteasome, and Bcl-2 family member inhibitors, among others. While most of these agents have been or are currently being evaluated in adult patients with acute leukemia, experience in childhood leukemia is very limited. Although the use of such targeted agents as potentiators of conventional cytotoxic agent activity represents a logical approach, an emerging body of evidence suggests that neoplastic cells in general, and leukemic cells in particular, are highly susceptible to a therapeutic strategy in which survival signaling and cell cycle regulatory pathways are simultaneously disrupted. In in vitro studies, highly synergistic antileukemic interactions have been reported between CDK and HDAC inhibitors; HDAC and proteasome inhibitors; Bcl-2 antagonists and CDK inhibitors; MEK/ERK and Chk1 inhibitors, and proteasome and CDK inhibitors, among other combinations. Some of these strategies, including combinations of HDAC and CDK inhibitors, and CDK and proteasome inhibitors, have now entered the clinical arena in patients with leukemia and other hematologic malignancies. Based upon preclinical results to date, there is reason to suspect that such strategies might prove to be active against several types of childhood leukemia. Thus, over the next decade, the introduction of molecularly targeted agents, alone and in combination, into the therapeutic armamentarium against childhood leukemia may have significant implications for children with this disease.
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PMID:Simultaneous interruption of signal transduction and cell cycle regulatory pathways: implications for new approaches to the treatment of childhood leukemias. 1758 30

Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Emu-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-XL inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-XL, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-XL was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities.
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PMID:Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin. 1848 96

Human multiple myeloma is a presently incurable hematological malignancy and novel biologically based therapies are urgently needed. Triptolide (TPL) is a purified diterpenod isolated from the Chinese herb, Tripterygium wilfordii Hook. F that has shown antitumor activities in various cancer cell types. But its activity in Dex-resistant multiple myeloma cell lines and the main upstream signaling pathway has not been reported. Here we show that TPL induces apoptosis in dexamethasone-sensitive (MM.1S) and dexamethasone-resistant (MM.1R) cells, most importantly its main upstream signaling pathway is through the PI3k/Akt/NF-kappaB pathway and is also associated with MAPK pathway, via mitochondrial apoptotic signaling and is also associated with the caspase and Bcl-2 family members. Moreover, TPL was able to enhance the activities of dexamethasone or bortezomib/PS-341 in multiple myeloma cell lines. Collectively, these findings provide the framework for a clinical evaluation of TPL, either alone or in combination with dexamethasone or bortezomib/PS-341, to overcome drug resistance and improve outcome for patients with this universally fatal hematological malignancy.
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PMID:Triptolide overcomes dexamethasone resistance and enhanced PS-341-induced apoptosis via PI3k/Akt/NF-kappaB pathways in human multiple myeloma cells. 1881 56

The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redox-related effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death.
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PMID:Oxidative stress by targeted agents promotes cytotoxicity in hematologic malignancies. 1901 67

The interaction between anti-apoptotic and pro-apoptotic members of the Bcl-2 family proteins determines life or death for cancer cells. In this context, BH3-only proteins (such as Bim), members of the pro-apoptotic Bcl-2 family proteins, act as key initiators of apoptosis by activating Bax and Bak through liberating them from anti-apoptotic Bcl-2 members. This then leads to the disruption of mitochondrial outer membrane, and eventually promotes proteolytic cascades for cellular dismantling. We here review the growing evidence of how BH3-only proteins are involved in tumorigenesis and in apoptosis induced by anti-cancer agents in hematologic malignancies. A deeper understanding of the roles of BH3-only proteins in cell death regulation may yield crucial insights for the further development of more effective and rational cell killing strategies. Recent developments in the direct therapeutic manipulation of Bcl-2 proteins using BH3-mimicking agents, such as ABT-737 or GX15-070, for hematologic malignancies are also summarized.
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PMID:Involvement of BH3-only proteins in hematologic malignancies. 1902 81

The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpression of Bcl-2 or Bcl-X(L). Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of Emu-myc lymphomas overexpressing Bcl-2 or Bcl-X(L) to vorinostat and valproic acid (VPA). Combining low-dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis of these cells. ABT-737 was ineffective against Emu-myc/Mcl-1 and Emu-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, Emu-myc/Bcl-w lymphomas were insensitive to ABT-737 used alone or in combination with HDACi, indicating that the regulatory activity of ABT-737 is restricted to Bcl-2 and Bcl-X(L). Emu-myc lymphomas that expressed Bcl-2 throughout the tumorigenesis process were especially sensitive to ABT-737, while those forced to overexpress Mcl-1 were not. This supports the notion that tumor cells "addicted" to ABT-737 target proteins (ie, Bcl-2 or Bcl-X(L)) are likely to be the most sensitive target cell population. Our studies provide important preclinical data on the binding specificity of ABT-737 and its usefulness against primary hematologic malignancies when used as a single agent and in combination with HDACi.
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PMID:Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. 1906 Feb 43

Mcl-1 (myeloid cell leukemia-1) is a member of Bcl-2 (B cell leukemia-2) family, which may play an important role in cell apoptosis regulation, occurrence and development of tumors. This paper reviews advance of studies on the function of the mcl-1 gene and MCL-1 protein, the signal transduction pathways (JAK/STAT, MAPK, PI-3K) regulating the expression of mcl-1 gene, and the relationship between mcl-1 gene and hematologic malignancies.
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PMID:[Progress of study on relationship between Mcl-1 gene and hematologic malignancies - review]. 1937

Loss of p53-dependent apoptosis contributes to the development of hematologic malignancies and failure to respond to treatment. Proapoptotic Bcl-2 family member Puma is essential for apoptosis in HoxB8-immortalized interleukin-3 (IL-3)-dependent myeloid cell lines (FDM cells) provoked by IL-3 deprivation. p53 and FoxO3a can transcriptionally regulate Puma. To investigate which transcriptional regulator is responsible for IL-3 deprivation-induced Puma expression and apoptosis, we generated wild-type (WT), p53(-/-), and FoxO3a(-/-) FDM cells and found that p53(-/-) but not FoxO3a(-/-) cells were protected against IL-3 withdrawal. Loss of p21(cip/waf), which is critical for p53-mediated cell-cycle arrest, afforded no protection against IL-3 deprivation. A survival advantage was also observed in untransformed p53(-/-) hematopoietic progenitor cells cultured in the presence or absence of cytokines. In response to IL-3 deprivation, increased Puma protein levels in p53(-/-) cells were substantially delayed compared with WT cells. Increased p53 transcriptional activity was detected after cytokine deprivation. This was substantially less than that induced by DNA damage and associated not with increased p53 protein levels but with loss of the p53 regulator, MDM2. Thus, we conclude that p53 protein is activated after IL-3 deprivation by loss of MDM2. Activated p53 transcriptionally up-regulates Puma, which initiates apoptosis.
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PMID:Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. 1996 65

Defects in apoptosis are observed in many cancer cell types and contribute in a relevant way to tumorigenesis. Apoptosis is a complex and well-regulated cell death program that plays a key role in the control of cell homeostasis, particularly at the level of the hematopoietic system. Apoptosis can be initiated through two different mechanisms involving either activation of the death receptors (extrinsic pathway) or activation of a mitochondrial apoptotic process (intrinsic pathway). Among the various death receptors a peculiar role is played by TNF-related apoptosis-inducing ligand (TRAIL)-receptors (TRAIL-Rs) and their ligand TRAIL. TRAIL recently received considerable interest for its potent anti-tumor killing activity, sparing normal cells. Here, we will review the expression and the abnormalities of TRAIL/TRAIL-R system in hematologic malignancies. The large majority of primary hematologic tumors are resistant to TRAIL-mediated apoptosis, basically due to the activation of anti-apoptotic signaling pathway (such as NF-kappaB), overexpression of anti-apoptotic proteins (such as FLIP, Bcl-2, XIAP) or expression of TRAIL decoy receptors or reduced TRAIL-R1/-R2 expression. Strategies have been developed to bypass this TRAIL resistance and are based on the combination of TRAIL with chemotherapy or radiotherapy, or with proteasome or histone deacetylase or NF-kappaB inhibitors. The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, XIAP, Bcl-2). Many of these combinatorial therapies hold promise for future developments in treatment of hematologic malignancies.
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PMID:TRAIL/TRAIL-R in hematologic malignancies. 2033 67

Differences in CD8(+)CD57(-) and CD8(+)CD57(+) lymphocyte lifespan have been documented. Lower numbers and shorter lifespan are characteristic of CD8(+)CD57(+) in normal individuals. However, CD8(+)CD57(+) are expanded in certain disease states including T cell large granular leukemia and other hematologic malignancies. The mechanisms responsible for the differences in CD8(+)CD57(-) and CD8(+)CD57(+) lifespan remain elusive. In this study, we demonstrate that the small heat shock protein (Hsp) 27 is a key regulator of CD8(+)CD57(+) lymphocyte lifespan. We found that Hsp27 expression is significantly lower in CD8(+)CD57(+) than in CD8(+)CD57(-) lymphocytes. In contrast, Hsp60 and Hsp70 are expressed at comparable levels. Unlike other antiapoptotic Bcl-2-like molecules, the expression of Hsp27 tightly correlates with CD8(+)CD57(+) and CD8(+)CD57(-) lifespan. We demonstrate that Hsp27 overexpression in CD8(+)CD57(+) lymphocytes to levels found normally in CD8(+)CD57(-) lymphocytes decreased apoptosis. Accordingly, silencing of Hsp27 in CD8(+)CD57(-) lymphocytes increased apoptosis. Collectively these results demonstrate that Hsp27 is a critical regulator of normal CD8(+)CD57(+) lifespan supporting its use as a marker of lifespan in this lineage, and suggest a mechanism responsible for the decreased apoptosis and clonal expansion characteristic of certain disease states.
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PMID:The small heat shock protein 27 is a key regulator of CD8+ CD57+ lymphocyte survival. 2038 76


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