Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that cotreatment with mitogen activated-protein kinase kinase (MEK) 1/2 inhibitors (e.g., PD184352) and the checkpoint abrogator 7-hydroxystaurosporine (UCN-01) dramatically induces apoptosis in a variety of human leukemia and multiple myeloma cell types. The purpose of this study was to evaluate the roles of Bcl-2 family members and the relative contribution of the intrinsic mitochondrial versus the extrinsic receptor-related apoptotic pathways to MEK inhibitors/UCN-01-induced leukemic cell death. Cotreatment of U937 cells with PD184352 and UCN-01 resulted in the activation of procaspase-3, -9, and -8 as well as Bid cleavage. PD184352/UCN-01-induced mitochondrial dysfunction and apoptosis were both substantially attenuated in cells ectopically expressing Bcl-2, an N-terminal phosphorylation loop-deleted mutant Bcl-2, or Bcl-xL, but not in cells expressing dominant-negative (DN) caspase-8, cytokine response modifier A (cowpox virus-encoded antiapoptotic protein), or DN Fas-associated death domain. Coadministration of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or TNF-alpha substantially increased MEK inhibitors (e.g., PD184352 or U0126)/UCN-01-induced mitochondrial dysfunction, activation of procaspase-8 and Bid, and apoptosis in Bcl-2- and Bcl-xL-overexpressing cells but not in those in which the extrinsic pathway was interrupted. Together, these findings suggest that the MEK inhibitors/UCN-01 regimen primarily induces leukemic cell apoptosis by engaging the intrinsic, mitochondrial apoptotic pathway and that resistance to these events conferred by increased expression of certain antiapoptotic Bcl-2 family members can be overcome, at least in part, by coadministration of TRAIL and other agents that activate the extrinsic apoptotic cascade.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes mitochondrial dysfunction and apoptosis induced by 7-hydroxystaurosporine and mitogen-activated protein kinase kinase inhibitors in human leukemia cells that ectopically express Bcl-2 and Bcl-xL. 1464 70

Interactions between histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand, were examined in human leukemia cells (e.g., U937, Jurkat, and HL-60). Simultaneous exposure of cells to 100-ng/ml TRAIL with either 1-mM sodium butyrate or 2- micro M suberoylanilide hydroxamic acid resulted in a striking increase in leukemic cell mitochondrial damage, caspase activation, and apoptosis. Lethal effects were significantly diminished in U937 cells ectopically expressing dominant-negative caspase-8, dominant-negative Fas-associated death domain, CrmA (receptor pathway), or Bcl-2 or Bcl-X(L) (mitochondrial pathway). Analysis of mitochondrial events in U937 cells exposed to TRAIL/HDAC inhibitors revealed enhanced Bid activation and Bax translocation, loss of mitochondrial membrane potential, and cytoplasmic release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor. No changes were observed in expression of FLICE-like inhibitory protein, TRAIL receptors, or reactive oxygen species generation. TRAIL/HDAC inhibitor-induced apoptosis triggered caspase-dependent cleavage of p21(WAF1/CIP1); moreover, enforced expression of a nuclear localization signal deletant form of p21(WAF1/CIP1) significantly diminished lethality. Lastly, p27(KIP1), pRb, X-linked inhibitor of apoptosis, and Bcl-2 displayed extensive proteolysis. These findings indicate that coadministration of TRAIL with HDAC inhibitors synergistically induces apoptosis in human myeloid leukemia cells and provide further evidence that simultaneous activation of the extrinsic and intrinsic pathways in such cells leads to a dramatic increase in mitochondrial injury and activation of the caspase cascade.
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PMID:Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. 1470 68

The bitter acids of hops (Humulus lupulus L.) mainly consist of alpha-acids, beta-acids, and their oxidation products that contribute the unique aroma of the beer beverage. Hop bitter acids displayed a strong growth inhibitory effect against human leukemia HL-60 cells, with an estimated IC(50) value of 8.67 microg/mL, but were less effective against human histolytic lymphoma U937 cells. Induction of apoptosis was confirmed in HL-60 cells by DNA fragmentation and the appearance of a sub-G1 DNA peak, which were preceded by dissipation of mitochondrial membrane potential, cytochrome c release, and subsequent induction of pro-caspase-9 and -3 processing. Cleavages of PARP and DFF-45 were accompanied with activation of caspase-9 and -3 triggered by hop bitter acids in HL-60 cells. The change in the expression of Bcl-2, Bcl-X(L), and Bax in response to hop bitter acids was studied, and the Bcl-2 protein level slightly decreased; however, the Bcl-X(L) protein level was obviously decreased, whereas the Bax protein level was dramatically increased, indicating that the control of Bcl-2 family proteins by hop bitter acids might participate in the disruption of mitochondrial integrity. In addition, the results showed that hop bitter acids promoted the up-regulation of Fas and FasL prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement of a Fas-mediated pathway in hop bitter acids-induced cells. Taken together, these findings suggest that a certain intimate link might exist between receptor- and mitochondria-mediated death signalings that committed to cell death induced by hop bitter acids. The induction of apoptosis by hop bitter acids may offer a pivotal mechanism for their chemopreventive action.
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PMID:Mechanisms of cancer chemoprevention by hop bitter acids (beer aroma) through induction of apoptosis mediated by Fas and caspase cascades. 1470 13

The marine alkaloid ascididemin (ASC) was shown to exert cytotoxicity even against multidrug-resistant cancer cells. Here, we address the signaling pathways utilized by ASC to trigger apoptosis in Jurkat leukemia T cells. We show that ASC (0.5-20 microM) induces a mitochondrial pathway that requires the activation of the initiator caspase-2 upstream of mitochondria. ASC-triggered apoptosis occurred independent of CD95, but required mitochondrial dysfunction. The activation of caspase-2 was shown to precede the processing of caspase-8, -9 and -3. The specific caspase-2 inhibitor zVDVADfmk abrogated ASC-induced DNA fragmentation almost completely. Overexpression of Bcl-x(L) blocked caspase-8 but not caspase-2 processing. Conversely, caspase-2 inhibition strongly reduced caspase-9 activation. As a possible link between caspase-2 and mitochondrial dysfunction, Bid was found to be cleaved by ASC. In addition, JNK was activated by ASC upstream of mitochondria via reactive oxygen species. The specific JNK inhibitor SP600125 partially inhibited caspase-2 and -9 processing as well as cytochrome c release and DNA fragmentation indicating that JNK contributes to, but is not necessary for ASC-mediated apoptosis. Thus, ASC triggers a pathway in which early activation of caspase-2 provides a possible link between its DNA-damaging activity and the induction of mitochondrial dysfunction. The activation of JNK contributes to this signaling upstream of mitochondria.
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PMID:Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondria. 1471

The functional significance of disruption of p21(WAF1/CIP1) induction by flavopiridol (FP) in human leukemia cells (Jurkat) exposed to the histone deacetylase (HDAC) inhibitor sodium butyrate (SB) was investigated. Coexposure of leukemic cells to FP blocked SB-mediated induction of p21(WAF1/CIP1) and resulted in a marked increase in mitochondrial injury, activation of procaspases-3 and -8, Bid cleavage, and PARP degradation. Enforced expression of p21(WAF1/CIP1) (i.e., in Jurkat cells inducibly expressing p21(WAF1/CIP1) under the control of a doxycycline-responsive promoter) partially but significantly reduced cytochrome c and apoptosis-inducing factor release, loss of mitochondrial membrane potential, caspase-3 and -8 activation, Bid cleavage, poly(ADP-ribose)polymerase (PARP) degradation, and apoptosis in response to SB/FP. Furthermore, increasing expression of p21(WAF1/CIP1) (i.e., by culturing cells in the presence of higher concentrations of doxycycline) rendered cells more resistant to SB/FP-mediated lethality. Enforced expression of p21(WAF1/CIP1) did not modify SB/FP-mediated JNK activation or generation of reactive oxygen species. Consistent with these results, Jurkat cells stably expressing a p21(WAF1/CIP1) nuclear localization mutant (p21DeltaNLS) were also resistant to SB/FP-mediated mitochondrial injury, activation of procaspases-3 and -8, PARP cleavage, and apoptosis. Finally, enforced expression of full-length or ectopic expression of DeltaNLS p21(WAF1/CIP1) increased the amount of p21(WAF1/CIP1) coimmunoprecipitating with procaspase-3. Together, these findings suggest that interruption of HDAC-mediated p21(WAF1/CIP1) induction by FP plays a significant functional role in potentiating apoptosis, possibly by preventing the formation of a procaspase-3/p21(WAF1/CIP1) complex.
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PMID:Evidence of a functional role for p21WAF1/CIP1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. 1497 35

Curcumin presents strong antioxidant and anticancer properties. However, molecular mechanisms leading to curcumin-induced cell death are poorly understood. The effect of curcumin was compared in two different leukemia cell lines: K562 and Jurkat. Cell death was induced in both cell lines, and apoptosis pathways were investigated by Western blot analysis. Decreases in pro-caspase 8 and 9 levels were observed. BH(3) interacting domain death agonist (Bid) was also cleaved. Jurkat cells appeared to be more sensitive to curcumin, and apoptosis takes place earlier.
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PMID:Curcumin-induced cell death in two leukemia cell lines: K562 and Jurkat. 1503 58

We previously reported that ent-11alpha-hydroxy-16-kauren-15-one (KD) induces apoptosis through a caspase-dependent pathway and the induction of apoptosis is dependent on its enone group in human leukemia cells. Here we investigated the abilities of some KD-related compounds with enone group (Fig. 1) to induce apoptosis and to activate some caspases. The IC50 values of ent-kaurene-related compounds possessing the enone group, ent-1beta-hydroxy-9(11),16-kauradien-15-one (1), ent-9(11),16-kauradiene-12,15-dione (2) and the rearranged ent-kaurane-type diterpene (3), against HL-60 cells after 12 h of treatment were 40 microM, 1.8 microM and 5.5 microM, respectively. Although treatment with 3 induced apoptosis, DNA ladder formation was not observed after treatment with 1 or 2. Induction of necrosis, as assayed by trypan blue staining, was observed after treatment with 1 or 2. Treatment with compound 1, 2 or 3 induced proteolysis of poly(ADP-ribose) polymerase (PARP), a substrate of caspase-3, and processing of caspase-3. Activation of caspase-8 and processing of Bid, a typical substrate of caspase-8, were also observed on treatment with these compounds. Pretreatment with a broad-spectrum inhibitor of caspases attenuated apoptosis induced by 3 but not necrosis induced by 1 and 2. In summary, KD-related compounds are a unique family of diterpenes that cause either caspase-dependent apoptotic or necrotic cell death.
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PMID:A comparison of apoptosis and necrosis induced by ent-kaurene-type diterpenoids in HL-60 cells. 1512 83

Previous studies by our laboratory have reported that the T cell receptor (TCR) TCR/CD3 complex could mediate activation as well as apoptosis of T lymphocytes. Two tyrosine residues in the ITAM (immuno-receptor tyrosine-based activation motifs) of CD3 epsilon were required for apoptosis signalling of Jurkat T lymphocytes. Stable cell lines TJK and T3JK produced from CD8(-) Jurkat T lymphocytes by transfection with wild-type and mutant CD8 epsilon (fusion of the extracellular and transmembrane domains of human CD8 alpha to the intracellular domain of mouse CD3 epsilon), were used with CD8(-) Jurkat T lymphocytes for studying the role of single intact CD3 epsilon. 5-Fluorouracil (5-FU), a chemotherapeutic drug can induce cell death of many tumour cell lines. In the present experiments, we examined the expression of caspase-3, p53 and Bid in the three cell lines induced by 5-FU and/or anti-CD8 antibody. We found high expression of p53 during activation-induced cell death of TJK cells mediated by anti-CD8 antibody and apoptosis of TJK and T3JK induced by 5-FU, implicating p53 involvement in apoptosis of leukemia cells induced by anti-CD8 antibody and 5-FU. We also detected the active form of caspase-3 and Bid in apoptotic leukemia cells after treatment with 5-FU and/or anti-CD8 antibody, indicating that the drug and antibody induced cell death through caspase-3 and the signal pathway may involve the Bcl-2 protein family. Our results showed that combined treatment with 5-FU and anti-CD8 antibody could enhance the rate of apoptosis induced by 5-FU or anti-CD8 antibody through increased expression of p53 and by promoting activation of caspase-3 and Bid. This suggests that the combination of 5-FU and anti-CD8 antibody may play an important role in inducing apoptosis of leukemia cells.
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PMID:5-Fluorouracil enhances apoptosis sensitivity of T lymphocytes mediated by CD3 epsilon. 1512 84

The role of mitochondria in cell death has been increasingly appreciated in the last few years and is now well established in a variety of cellular systems. At present we know that the involvement of mitochondria is regulated by proteins of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family, which biochemically act by altering the properties of mitochondrial membranes to facilitate the release of apoptogenic proteins like cytochrome c and Smac/Diablo that, once released into the cytosol, are crucial for activating the caspase cascade of cell degradation. The precise mechanism of the pro-apoptotic action is not fully understood yet, but could be clarified in the near future. Instrumental to this clarification is the emerging evidence that CL (cardiolipin), an unusual membrane lipid that is predominantly present in mitochondria, is required for the action of major pro-apoptotic proteins like Bid and Bax. New results obtained in myeloid cells further sustain this possibility and suggest that Bid may be involved in the metabolic cycle of CL re-modelling. In agreement with this postulate, preliminary results indicate a down-regulation of Bid in parallel to the genetic deficiency in CL re-modelling that is associated with a rare human disease, 'Barth Syndrome'. Intriguingly, this disease is characterized by neutropenia, suggesting a link between myeloid differentiation and cell death (and myeloid lymphoma pathogenesis too). I will project current results and trends towards future investigations on the involvement of CL and mitochondrial membranes in myeloid differentiation, cell death and disease.
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PMID:Mitochondria in apoptosis: past, present and future. 1515 69

Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24 h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-induced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-x(L), or a phosphorylation loop-deleted form of Bcl-2 (DeltaBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FP-mediated XIAP downregulation.
Leukemia 2004 Nov
PMID:Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. 1538 34


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