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 mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.
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PMID:Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. 1156 Sep 54

Genasense (formerly known as G-3139), an antisense oligonucleotide specific for Bcl-2, is under development by Genta as an iv drip infusion for the potential treatment of various cancers including melanoma, prostate, breast and colon cancer [3083751. It is in phase III trials for malignant melanoma, for which it has been awarded Fast Track status 1359044]. Genasense received Orphan Drug status in August 2000 [3782331. In September 2000, the company announced that pivotal phase III trials in multiple melanoma, chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML) would be underway by 2001 [382783]. By January 2001, trials in AML and CLL had been initiated 1396512]. As of February 2001, Genta was planning the initiation of two additional, registration quality trials. Pending positive results from these trials, launch of Genasense is anticipated in 2002 13984111. A phase III trial in patients with advanced multiple myeloma at 65 centers in the US, Canada and Great Britain began in February 2001. The trial will examine whether the addition of Genasense can improve response rates, response duration and quality of life compared with dexamethasone therapy alone 13989081. Genta Inc has been issued a patent (US-05831066) for Genasense 1283005]. The patent provides protection to Genta for the composition of Genasense and its analogs. Furthermore, Genta Inc has also been issued two new patents that cover a series of compounds containing new backbone constructions that enhance the antisense affinity of the drug to the target pre-RNA, while the other patent covers the methods for preparation of antisense oligonucleotides containing the new backbone structures 12896851. Genta has already licensed the rights for the use of Bd-2 as a target for antisense- and gene therapy-based treatments from The University of Pennsylvania. The licensing agreements with Chugai Pharmaceutical Co for worldwide marketing and profit sharing places Genta in a favorable position. In January 2001, Needham & Co expected Genasense to have a potential market of 47,700 malignant melanoma patients in the US. The analysts also expected potential patient market sizes of 50,000 (CLL), 21,000 (AML), 136,000 (non-small cell lung cancer; NSLCC) and 180,000 (prostate cancer) in the US. In addition, the analysts predicted that Genasense would be approved for melanoma in the second quarter of 2002, with approvals to follow for CLL (third quarter of 2002), AML (third quarter of 2002) and myeloma (fourth quarter of 2002) 1399251].
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PMID:Genasense (Genta Inc). 1156 20

Deregulated expression of the proto-oncogene c-myb, which results from provirus integration, is thought to be responsible for transformation in a set of murine leukemia virus (MuLV)-induced myeloid leukemias (MML). We reported recently that this transcription factor promotes proliferation by directly transactivating c-myc and inhibits cell death through its up-regulation of Bcl-2 (Schmidt et al., 2000). To understand more about how these cells become transformed we looked at how they deal with cellular pathways inducing growth arrest. Specifically, we were interested in the expression of the tumor suppressor gene Cdkn2b (p15(INK4b)) in MML because this gene is expressed during myeloid differentiation and its inactivation by methylation has been shown to be important for the development of human acute myeloid leukemia. mRNA levels for p15(INK4b) and another INK4 gene p16(INK4a) were examined in monocytic Myb tumors and were compared with expression of the same genes in c-myc transformed monocytic tumors that do not express c-Myb. The Cdkn2a (p16(INK4a)) gene was generally not expressed in either tumor type, an observation explained by methylation or deletion in the promoter region. Although Cdkn2b (p15(INK4b)) mRNA was expressed in the Myc tumors, many transcripts were aberrant in size and contained only exon 1. Surprisingly, in the majority of the Myb tumors there was no p15(INK4b) transcription and neither deletion nor methylation could explain this result. Additional experiments demonstrated that, in the presence of constitutive c-Myb expression, the induction of p15(INK4b) mRNA that accompanies differentiation of M1 cells to monocytes does not occur. Therefore, the transcriptional regulator c-Myb appears to prevent activation of a growth arrest pathway that normally accompanies monocyte maturation.
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PMID:Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15(INK4b) normally associated with differentiation. 1159 29

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

Like Bcl-2, peripheral benzodiazepine receptors (pBzRs) reside in mitochondrial pores, are frequently over-expressed in tumor cells, and can protect cells from apoptotic cell death. We now show that the high-affinity, pBzR-specific ligand, PK11195, chemosensitizes AML cells to relevant chemotherapeutics, but is relatively non-toxic as a single agent, and does not chemosensitize normal myeloid cells. PK11195 can block p-glycoprotein efflux in AMLs, contributing to increased daunomycin toxicity in efflux-competent AMLs, but can also sensitize AMLs to cytarabine and DNR-sensitize efflux-incompetent AMLs, presumably via mitochondrial pore effects documented in other models. Therefore, PK11195 might contribute to improved clinical outcomes in AML.
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PMID:PK11195, a peripheral benzodiazepine receptor ligand, chemosensitizes acute myeloid leukemia cells to relevant therapeutic agents by more than one mechanism. 1173 7

It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1-overexpressing, p53(null) HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34(+) progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1- and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
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PMID:Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. 1175 88

Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that has been shown to inhibit the proliferation of a wide variety of tumor cells. The apoptotic intermediates through which curcumin exhibits its cytotoxic effects against tumor cells are not known, and the participation of antiapoptotic proteins Bcl-2 or Bcl-xl in the curcumin-induced apoptosis pathway is not established. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human acute myelogenous leukemia HL-60 cells and in established stable cell lines expressing Bcl-2 and Bcl-xl. Curcumin inhibited the growth of HL-60 cells (neo) in a dose- and time-dependent manner, whereas Bcl-2 and Bcl-xl-transfected cells were relatively resistant. Curcumin activated caspase-8 and caspase-3 in HL-60 neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Similarly, time-dependent poly(ADP)ribose polymerase (PARP) cleavage by curcumin was observed in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Curcumin treatment also induced BID cleavage and mitochondrial cytochrome c release in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. In neo HL-60 cells, curcumin also downregulated the expression of cyclooxygenase-2. Because DN-FLICE blocked curcumin-induced apoptosis, caspase-8 must play a critical role. Overall, our results indicate that curcumin induces apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Our results also suggest that Bcl-2 and Bcl-xl are critical negative regulators of curcumin-induced apoptosis.
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PMID:Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. 1175 35

While studying Ikaros proteins in childhood acute myeloid leukemia (AML), Ikaros isoform 6 (Ik6) expression was detected in 7 of 10 cases of M4 and M5 leukemia, but in none of the remaining French-American-British subtypes (M2, 8 cases; M7, 6 cases). The spliced Ikaros isoforms 4 to 8 (Ik4-8) suppress the function of full-length Ik1 or Ik2 in a dominant-negative manner, owing to their reduced numbers of DNA binding sites. Thus, dominant-negative Ikaros isoforms may inhibit the normal transcriptional regulation of hematopoietic cell development. To clarify the function of Ik6 in developing blood cells, this isoform was transiently transfected into an Ik2(+), interleukin-3 (IL-3)-dependent 32D murine myeloid precursor cell line and studied the expression of Bcl-2 family proteins in relation to in vitro cell growth, using a tetracycline-inducible TREx system. The possibility of aberrant cell regulation due to Ikaros functional changes was examined by cotransfecting both Ik2 and Ik6 into Ikaros/Aiolos/Helios triple-negative Cos-7 cells. The results demonstrated IL-3-independent growth by Ik6-transfected 32D clones coincident with up-regulation of the antiapoptotic protein Bcl-XL. Up-regulation of Bcl-XL, but not of other Bcl-2 family proteins, was associated with the suppression of functional Ik2 by Ik6 in a dominant-negative fashion. Thus, the pathogenesis of myelomonocytic/monocytic AML may involve aberrant regulation of apoptosis due to unscheduled expression of the Ik6 isoform.
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PMID:High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis. 1241 79

The search for molecular markers in AML that allow prediction of outcome has recently focused on genes involved in the regulation of programmed cell death (PCD). The aim of our study was to determine whether mRNA levels of Mdm-2, Bcl-2, Bcl-x(L), Bad, and Bax are independent prognostic parameters for outcome. Transcript levels were analyzed by real-time quantitative RT-PCR in 232 samples collected either at diagnosis or following induction chemotherapy (ICT). Multivariate COX regression analysis adjusted for chemotherapy protocol, de novo vs secondary AML, and de novo vs relapsed AML indicated: (1) At diagnosis, high expression of Bad (P = 0.015) and even more so high Bax and Bad levels (P = 0.018) predicted adverse outcome, regardless of the response to ICT. In patients who subsequently failed to enter complete remission (CR), high levels of Bad, Bax and Bax high/Bad high were associated with an increased relative risk (RR) to die from tumor (RR = 5.0 for Bad, 3.4 for Bax and 6.14 for Bax high/Bad high). (2) Following ICT, high expression of Bax (P= 0.005) and high Bcl-2/Bax ratios (P = 0.004) were independent predictors of unfavorable outcome, regardless of response to ICT. We conclude that high levels of Bax and Bad correlate with poor outcome, particularly in patients who do not enter CR and may serve as prognostic markers in AML.
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PMID:High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML). 1184 Feb 59

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the latest members of the TNF superfamily known to induce apoptosis in a wide variety of tumor cells. Some cell types, however, are quite resistant to TRAIL. We investigated the effect of ectopic expression of Bcl-2 and Bcl-xL on TRAIL-induced apoptosis in human acute myelogenous leukemia HL-60 cells. We found that HL-60 cells, which express TRAIL receptors (also called death receptor, DR) DR4, DR5, and Dc (decoy) R2, are highly sensitive to TRAIL-induced cytotoxicity. Greater than 90% killing occurred within 24 h of TRAIL treatment. The expression of Bcl-2 and Bcl-xL, however, completely abolished the TRAIL-induced cytotoxic effects. Treatment of HL-60 cells with TRAIL induced caspase-8 activation within 2-4 h, but no activation could be seen in Bcl-2-expressing or Bcl-xL-expressing cells. TRAIL also induced cleavage of BID, which was also abolished by Bcl-2 and Bcl-xL. Similarly, TRAIL activated caspase-3 and caspase-7 in control cells but not in cells expressing Bcl-2 or Bcl-xL. Cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), was abrogated by ectopic expression of Bcl-2 and Bcl-xL. Inhibition of caspases by the pan-caspase inhibitor, benzyloxycarbonyl-valine-alanine-aspartate-fluoromethylketone (zVAD-fmk) abolished the TRAIL-induced apoptosis. Overall, these results indicate that TRAIL-induced apoptosis involves activation of caspase-8, caspase-7, caspase-3, and BID cleavage, and Bcl-2 and Bcl-xL prevents TRAIL-induced apoptosis by abrogating caspase activation and BID cleavage.
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PMID:Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60. 1191 10


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