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)

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Ph1-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappa B inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5 expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These results suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias.
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PMID:TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. 1250 34

Endogenous cellular chromophores absorb ultraviolet A radiation (UVA, 290-320 nm), the major UV component of terrestrial solar radiation, leading to the formation of reactive oxidizing species that initiate apoptosis, gene expression and mutagenesis. UVA-induced apoptosis of T helper cells is believed to underlie the UVA phototherapy for atopic dermatitis and other T cell-mediated inflammatory skin diseases. We have evaluated the involvement of the Fas-Fas ligand (FasL) pathway in rapid UVA-induced apoptosis in human leukemia HL-60 cells. UVA-induced apoptosis was not inhibited by pretreatment with a neutralizing anti-Fas antibody, although the same UVA treatment initiated cleavage of caspase-8 and subsequent processing of Bid and caspase-3-like proteases. Inhibition of caspase-8 by Lle-Glu (OMe)-Thr-Asp(OMe)-fluoromethyl ketone completely blocked caspase-3 cleavage and apoptosis in UVA-treated cells, suggesting that apoptosis was initiated by the Fas pathway. This inference was supported by demonstrating that immunoprecipitates obtained from UVA-treated cells using anti-Fas antibody contained caspase-8 and Fas-associating protein with death domain (FADD). In addition, Fas clustering in response to UVA treatment was observed by immunofluorescence microscopy. These data support a mechanism for rapid, UVA-induced apoptosis in HL-60 cells involving initial formation of the Fas-FADD-caspase-8 death complex in an FasL-independent manner.
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PMID:Ultraviolet A radiation induces rapid apoptosis of human leukemia cells by Fas ligand-independent activation of the Fas death pathways. 1292 50

DNA-damaging reagents may kill tumor cells through the generation of reactive oxygen species (ROS). Cytotoxic reagents may also induce apoptosis of cancer cells in Fas-FADD-dependent manners. In this study, we explored the possible link between these two apparently distinct pathways in T leukemia cell Jurkat. Our results demonstrated that gamma-irradiation, similar to cisplatin, induced apoptosis by triggering Fas aggregation and activating FADD-caspase-8 apoptotic cascade. The absence of caspase-8 or Fas greatly reduced the sensitivity to apoptosis mediated by DNA-damaging agents. In addition, apoptosis induced by cisplatin and gamma-irradiation, but not by Fas, was inhibited by ROS scavengers, including N-acetyl cysteine, MnTBAP, and C60. Importantly, these ROS scavengers effectively prevented the clustering of Fas receptor induced by cisplatin and gamma-irradiation. Our results suggest that cisplatin and gamma-irradiation promote ROS production, which in turn contributes to Fas receptor aggregation and cell death. The novel coupling between ROS and Fas clustering likely plays a significant role in apoptosis triggered by DNA-damaging reagents in Fas-expressing leukemia cells.
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PMID:DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation. 1460 57

The peroxisome-proliferator-activated receptor (PPAR) gamma agonist, CDDO, is under investigation for use in various malignancies. The mechanisms by which CDDO induces apoptosis are controversial. We have therefore sought to determine these mechanisms using primary chronic lymphocyte leukemic (CLL) cells and Jurkat cell lines with defined apoptotic abnormalities. In these cells, CDDO induced-apoptosis involved caspase-independent loss in mitochondrial membrane potential followed by caspase processing. The pattern of CDDO-induced caspase processing, defined by use of a caspase inhibitor, strongly suggested that caspase-9 was the apical caspase. Moreover, CDDO induced apoptosis in caspase-8 and FADD-deficient but not in Bcl-xL overexpressing Jurkat cells. In CLL cells, CDDO induced an early release of mitochondrial cytochrome c and Smac that preceded apoptosis. Thus, in both cell types, CDDO induced apoptosis primarily by the intrinsic pathway with caspase-9 as the apical caspase. This has important implications in the design of novel agents for the treatment of CLL and other malignancies.
Leukemia 2004 May
PMID:CDDO induces apoptosis via the intrinsic pathway in lymphoid cells. 1499 Sep 79

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

Inhibitors of serine/threonine protein phosphatases can inhibit apoptosis. We investigated which protein phosphatases are critical for this protection using calyculin A, okadaic acid, and tautomycin. All three phosphatase inhibitors prevented anisomycin-induced apoptosis in leukemia cell models. In vitro, calyculin A does not discriminate between PP1 and PP2A, while okadaic acid and tautomycin are more selective for PP2A and PP1, respectively. Increased phosphorylation of endogenous marker proteins was used to define concentrations that inhibited each phosphatase in cells. Concentrations of each inhibitor that prevented anisomycin-induced apoptosis correlated with inhibition of PP2A. The inhibitors prevented Bax translocation to mitochondria, indicating inhibition upstream of mitochondria. Tautomycin and calyculin A, but not okadaic acid, also prevented apoptosis induced through the CD95/Fas death receptor, and this protection correlated with inhibition of PP1. The inhibitors prevented Fas receptor oligomerization, FADD recruitment, and caspase 8 activation. The differential effects of PP1 and PP2A in protection from death receptor and mitochondrial-mediated pathways of death, respectively, may help one to define critical steps in each pathway, and regulatory roles for serine/threonine phosphatases in apoptosis.
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PMID:Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. 1545 40

The transplantation of pancreatic islets for the treatment of type I diabetes is hindered by the enormous loss of cells due to early apoptotic events. Genetic engineering of islets with cytoprotective genes is an important strategy aimed to enhance the survival of these cells in the transplant setting. The present study was designed to evaluate and compare the effects of five genes on a cell line derived from insulin-producing beta-cells, NIT-1. Cells were transduced using a Maloney murine leukemia virus (MLV) vector coding for yellow fluorescent protein (YFP) and for one of the following antiapoptotic genes: cFLIP, FADD-DN, BcL-2, PI-9, and ICAM-2. These genes were able to protect NIT-1 cells from cytokine-induced apoptosis to varying degrees ranging from no protection to significant protection equivalent to an optimal dose of a chemical caspase inhibitor. The data demonstrate that cFLIP, FADD-DN, and PI-9 are significantly more effective in protecting NIT-1 cells than BcL-2 and ICAM-2. Additionally, the data show that despite its weak in vitro inhibition of caspase-3, PI-9 affords significant protection against TNF-alpha-induced apoptosis in these cells. These genes may be ideal candidates to augment islet survival following transplantation.
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PMID:Retrovirally transferred genes inhibit apoptosis in an insulin-secreting cell line: implications for islet transplantation. 1556 61

Targeting cannabinoid receptors has recently been shown to trigger apoptosis and offers a novel treatment modality against malignancies of the immune system. However, the precise mechanism of apoptosis in such cancers has not been previously addressed. In this study, we used human Jurkat leukemia cell lines with defects in intrinsic and extrinsic signaling pathways to elucidate the mechanism of apoptosis induced by Delta9-tetrahydrocannabinol (THC). We observed that Jurkat cells deficient in FADD or caspase-8 were partially resistant to apoptosis, while dominant-negative caspase-9 mutant cells were completely resistant to apoptosis. Use of caspase inhibitors confirmed these results. Furthermore, overexpression of Bcl-2 rendered the cells resistant to THC at early time points but not upon prolonged exposure. THC treatment led to loss of Deltapsi(m), in both wild-type and FADD-deficient Jurkat cells thereby suggesting that THC-induced intrinsic pathway was independent of FADD. THC treatment of wild-type Jurkat cells caused cytochrome c release, and cleavage of caspase-8, -9, -2, -10, and Bid. Caspase-2 inhibitor blocked THC-induced caspase-3 in wild-type Jurkat cells but not loss of Deltapsi(m). Together, these data suggest that the intrinsic pathway plays a more critical role in THC-induced apoptosis while the extrinsic pathway may facilitate apoptosis via cross-talk with the intrinsic pathway.
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PMID:Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. 1597 42

Programmed cell death, or apoptosis, is a physiological means of eliminating unwanted cells and maintaining immune homeostasis. One of the primary mechanisms is the Fas (CD95)/Fas ligand system. Its inactivation in normal cells and malignant cells may be involved in malignant trans-formation and refractory clinical course, respectively. We established a Fas resistant clone and evaluated the molecular basis for its mechanism of resistance. The Fas-sensitive leukemia cell line, MML-1, was established from a child with B-precursor acute lymphoblastic leukemia. A Fas resistant clone, MML-1R, was obtained by co-culture selection with anti-Fas antibody CH-11. Flow cytometry analysis showed both cell lines had equivalent expression of cell surface CD13, 15, 19, 22 and Fas receptor. Western blot analysis revealed equal expression of FADD (Fas-associated death domain protein), caspase-3 and -8. MML-1 was quite sensitive to both CH-11 and etoposide-induced apoptotis. By contrast, MML-1R had similar sensitivity to etoposide but no response to CH-11. Fas receptor mutation analysis showed a heterozygous death domain A --> G point mutation at 1009 bp, causing a switch from glutamine to glycine at amino acid 256. Immunoprecipitation assay showed decreased binding of Fas to FADD. We also found that etoposide bypassed Fas-FADD interaction in MML-1R by activating caspase-8 and caspase-3. These results indicate that Fas resistance can result from mutations of the gene encoding the Fas receptor which result in decreased FADD binding, thereby blocking formation of the death inducing signaling complex. Screening for similar Fas mutations in therapy resistant malignancies would lead to a better understanding of tumorigenesis and recurrence.
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PMID:Acquisition of Fas resistance by Fas receptor mutation in a childhood B-precursor acute lymphoblastic leukemia cell line, MML-1. 1601 Apr 41

Apoptin, a small proline-rich protein derived from the chicken anaemia virus, induces cell death selectively in cancer cells. The signalling pathways of apoptin-induced, cancer cell-selective apoptosis are not well understood. Here, we demonstrate that apoptin triggers apoptosis by activating the mitochondrial/intrinsic pathway, and that it acts independently of the death receptor/extrinsic pathway. Jurkat cells deficient in either FADD or caspase-8 (which are both necessary for the extrinsic pathway) were equally as sensitive to apoptin as their parental clones. This demonstrates that apoptin is likely to act through the mitochondrial death pathway. Apoptin treatment causes a loss of mitochondrial membrane potential, and release of the mitochondrial proteins cytochrome c and apoptosis-inducing factor. Apoptin-induced cell death is counteracted by the anti-apoptotic Bcl-2 family members, Bcl-2 itself and Bcl-XL, as shown in Jurkat leukaemia cells. In addition, we describe the processing and activation of caspase-3. By contrast, cleavage of caspase-8, which is predominantly triggered by the death receptor pathway, is not observed. Furthermore, apoptin triggers the cytoplasmic translocation of Nur77, and the inhibition of Nur77 expression by siRNA significantly protects MCF7 cells from apoptin-triggered cell death. Thus, our data indicate that the apoptin death signal(s) ultimately converges at the mitochondria, and that it acts independently of the death receptor pathway.
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PMID:Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway. 1617 7


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