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)

The hydrophobic photosensitising agent meta-tetrahydroxyphenylchlorin (m-THPC) must be formulated with an appropriate vehicle before administration. Studies were carried out with murine leukaemia cells in vitro to assess the role of formulation in drug pharmacokinetics. The rate-limiting step in m-THPC accumulation was the slow conversion of drug aggregates to monomers upon dilution into growth media. Only non-viable cells with damaged membranes showed a rapid drug uptake, otherwise m-THPC accumulation was a slow process. It was found that m-THPC was localised mainly at mitochondrial loci. Subsequent irradiation resulted in the release of cytochrome c into the cytosol, triggering a rapid activation of caspase-3, which led to an apoptotic response. Plasma distribution of m-THPC involved binding to lipoprotein species, with only a slight appearance of the drug in the albumin fraction.
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PMID:Transport and localisation of m-THPC in vitro. 1056 69

The aim of this study was to investigate the mechanism of flavonoid-induced apoptosis in HL-60 leukaemic cells. Thus, the effect of structurally related flavonoids on cell viability, DNA fragmentation and caspase activity was assessed. Loss of membrane potential and reactive oxygen species generation were also monitored by flow cytometry. The structurally related flavonoids, such as apigenin, quercetin, myricetin, and kaempferol were able to induce apoptosis in human leukaemia HL-60 cells. Treatment with flavonoids (60 microM) caused a rapid induction of caspase-3 activity and stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP). Furthermore, these flavonoids induced loss of mitochondrial transmembrane potential, elevation of reactive oxygen species (ROS) production, release of mitochondrial cytochrome c into the cytosol, and subsequent induction of procaspase-9 processing. The potency of these flavonoids on these features of apoptosis were in the order of: apigenin > quercetin > myricetin > kaempferol in HL-60 cells treated with 60 microM flavonoids. These results suggest that flavonoid-induced apoptosis is stimulated by the release of cytochrome c to the cytosol, by procaspase-9 processing, and through a caspase-3-dependent mechanism. The induction of apoptosis by flavonoids may be attributed to their cancer chemopreventive activity. Furthermore, the potency of flavonoids for inducing apoptosis may be dependent on the numbers of hydroxyl groups in the 2-phenyl group and on the absence of the 3-hydroxyl group. This provides new information on the structure-activity relationship of flavonoids.
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PMID:Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. 1067 81

Affinity labeling showed that active caspases with molecular masses of 20 kDa, 19 kDa, and 17 kDa were formed upon treatment of human leukemia U937 cells with GGO. These caspases are quite similar to those activated by treatments with other apoptosis-inducers, such as VP16 and camptothecin, suggesting that similar caspases, such as caspases 3 and 6, are activated during apoptosis in U937 cells that is induced by a variety of apoptosis-inducing stimuli. An inhibitor of caspases, Z-Asp-CH2DCB, inhibited DNA fragmentation in response to GGO in vivo by blocking the cleavage of 20-kDa to 17-kDa peptides. This cleavage is catalyzed by caspase 3 itself or by a caspase-3-like protease. In contrast, other inhibitors of caspases such as Z-DEVD-FMK and Z-VAD-FMK, inhibited the processing of the caspase 3 precursor p32 to 20-kDa and 17-kDa peptides, a result which suggests that these inhibitors inhibited other upstream caspases. Treatment of U937 cells with GGO resulted in the release of cytochrome c from mitochondria prior to DNA fragmentation and the release of cytochrome c was inhibited by Zn2+ ions and by a chelator of Ca2+ ions but not by inhibitors of caspases such as Z-Asp-CH2DCB or Z-VAD-FMK. These results suggest that intracellular free Ca2+ ions, and some caspases that are inhibited by Zn2+ ions, but not by Z-Asp-CH2DCB or Z-VAD-FMK are necessary for the release of cytochrome c that is caused by the treatment with GGO.
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PMID:Analysis of caspases that are activated during apoptosis in leukemia U937 cells in response to geranylgeraniol. 1069 11

The efficacy of taxanes on human leukemia cells is the object of intensive in vitro investigation concerning the influence of cell-type-specific characteristics on cytotoxic response to drugs. The present study dissects the response to taxanes of HL60 acute myelomonocytic leukemia and of K562 chronic myelogenous leukemia, in parallel over a 72-hr time-span. The kinetics of cytotoxicity following pulsed and continuous exposure to either taxol or taxotere showed a delayed response of K562 cells independently of dose and type of exposure. In K562 cells, apoptosis became evident at 48 hr and prominent at 72 hr of treatment. These events were mirrored by delayed kinetics of caspase-3 activation. Comparable microtubule targeting was demonstrated in HL60 and in K562 cell lines, as bcl-2 and raf-1 were phosphorylated following treatment with taxanes. These observations indicate that early activation processes were responsible for apoptosis, but that the delay was determined by other factors. In addition, cell-free-system experiments excluded the presence of excess nuclear and/or cytoplasmic inhibitory factors and demonstrated that K562 cells possess a fully competent caspase system which can be readily activated. Processing of caspase-3 pro-enzyme was in fact increased by addition of cytochrome c. These results extend to taxol and taxotere the notion that drug-induced apoptosis is delayed upstream of caspase-3 activation in K562 cells, that such kinetics is independent of drug concentration and exposure time, and that it is linked to intrinsic cellular characteristics mapping between bcl-2 phosphorylation and cytochrome c release.
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PMID:Late apoptotic effects of taxanes on K562 erythroleukemia cells: apoptosis is delayed upstream of caspase-3 activation. 1069 26

6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel compound that represents the prototype of a new class of synthetic retinoids with apoptogenic properties in acute promyelocytic leukemia (APL) and other types of leukemia. In this article, using SCID mice xenografted with APL-derived NB4 cells, we demonstrate that CD437 has significant antileukemic activity in vivo. In addition, we report on the isolation and characterization of an APL cell line (NB4.437r) resistant to CD437. The cell line retains expression of PML-RARalpha and is approximately 33-fold more resistant than the parental counterpart to the apoptogenic effects of the retinoid. Resistance is relatively specific to CD437 and structural congeners because the NB4.437r cell line is still sensitive to various types of apoptogenic compounds. The CD437-resistant cell line maintains sensitivity to the antiproliferative and apoptotic action of all-trans-retinoic acid, AM580, and fenretinide, though it shows partial resistance to the cytodifferentiating effects of the first 2 compounds. Resistance to CD437 lays upstream of the CD437-induced release of cytochrome c from the mitochondria and the activation of caspase-3, -7, -8, and -9. Furthermore, NB4.437r cells are deficient in the CD437-dependent activation of nuclear NFkb and AP1-binding activities and in the phosphorylation of the protein kinase Akt. In the case of AP1, deficient assembly of the complex is not caused by the lack of activation of the Jun N-terminal kinase (JNK) family of kinases. The novel cell line will be useful in the elucidation of the molecular mechanisms underlying the apoptogenic action of CD437 and structurally related retinoids. (Blood. 2000;95:2672-2682)
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PMID:Isolation and characterization of an acute promyelocytic leukemia cell line selectively resistant to the novel antileukemic and apoptogenic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid. 1075 50

We investigated the possible roles of mitochondrial manganese superoxide dismutase (MnSOD) and bcl-2 in etoposide-induced cell death in acute myeloblastic leukaemia (AML) using two subclones of the OCI/AML-2 cell line, the etoposide-sensitive (ES) and the etoposide-resistant (ER), as models. Cell death after 24 h exposure to 10 micromol/l etoposide was about 60% and 70% in the ES subclone and about 20% and 25% in the ER subclone, when analysed by trypan blue and annexin V respectively. Cytochrome c efflux from mitochondria to cytosol was observed after 4 h of exposure in both subclones, whereas the activation of caspase-3 was not detectable until after 12 h of exposure in the ES subclone and 24 h of exposure in the ER subclone, using Western blotting. The decrease in mitochondrial membrane potential, when analysed by the JC-1 probe fluorocytometrically, also appeared to take place later in the ER than in the ES subclone. Both subclones showed evident basal expression of MnSOD and bcl-2 by Western blotting. Etoposide caused a potent induction of MnSOD, more than 400% at 12 h, in the ER but not in the ES subclone. No significant change in bcl-2 expression could be observed in either of the subclones during exposure to etoposide when analysed by Western blotting or flow cytometry. In conclusion, we suggest that MnSOD might have a special role in the protection of AML cells against etoposide-induced cell death. Although unable to influence the cytochrome c efflux to cytosol, MnSOD might prevent the disruption of mitochondrial membrane potential, which evidently leads to cell death by releasing various activators of apoptosis.
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PMID:Induction of mitochondrial manganese superoxide dismutase confers resistance to apoptosis in acute myeloblastic leukaemia cells exposed to etoposide. 1075 16

Exposure of murine leukemia L1210 cells to the antitumor antibiotic cryptophycin 52 (C52) led to cell-cycle arrest at the prometaphase/metaphase interface within 18 h, but apoptotic nuclei did not appear until 36 h later. To determine whether accumulation of cells in early metaphase might have delayed the apoptotic process, cells were treated with C52 for 18 h and a photodynamic process was used to initiate the release of mitochondrial cytochrome c. Apoptosis was observed within 60 min, indicating that the slow apoptotic response was not caused by an impaired ability of genomic DNA to undergo endonucleosomal cleavage during cell-cycle arrest induced by cryptophycin 52.
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PMID:Cells in cryptophycin-induced cell-cycle arrest are susceptible to apoptosis. 1076 19

Apoptosis induced by proteasome inhibitor in human THP-1 leukemia cells is associated with the cleavage of Bcl-2 into a shortened fragment, Bcl-2/Delta34. Both Bcl-2 and its cleaved fragment were located exclusively on the mitochondria of THP-1 cells. No translocation of Bcl-2 or Bcl-2/Delta34 to the cytosolic fraction was detected during apoptosis. Treatment of isolated mitochondria with recombinant caspase-3 induced the same cleavage of Bcl-2 in vitro and triggered the release of cytochrome c from the mitochondria. The ability of Bcl-2/Delta34 in regulating the opening of membrane "pores" was investigated using a sheep red blood cell (RBC) model with in vitro translated Bcl-2/Delta34 and Bcl-2 proteins. Bcl-2 and Bcl-2/Delta34 generated in vitro were relocated rapidly to sheep RBC but caused no hemoglobin release in either case. Addition of anti-Bcl-2 antibodies directly to the RBC that had been loaded with either Bcl-2 or Bcl-2/Delta34 resulted in a rapid release of hemoglobin from the blood cells. Treatment of the sheep RBC with anti-Bcl-2 or anti-sheep RBC antibodies alone did not trigger hemoglobin release from the RBC. Based on these findings, we proposed that, upon "enforced aggregation," both Bcl-2 and Bcl-2/Delta34 can form "pores" in membranes, which may contribute to the release of cytochrome c in apoptosis.
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PMID:Bcl-2 antibodies induce hemoglobin release by red blood cells loaded with in vitro translated Bcl-2 and its cleaved fragment. 1077 8

Nitric oxide (NO) from (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1,2-diolate (NOC-18) induces apoptosis in human leukemia HL-60 cells. This effect was prevented by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK), thereby implicating caspase activity in the process. NOC-18 treatment resulted in the activation of several caspases including caspase-3, -6, -8, and -9(-like) activities and the degradation of several caspase substrates such as nuclear lamins and SP120 (hnRNP-U/SAF-A). Moreover, release of cytochrome c from mitochondria was also observed during NOC-18-induced apoptosis. This change was substantially prevented by Z-VAD-FMK, thereby suggesting that the released cytochrome c might function not only as an initiator but also as an amplifier of the caspase cascade. Bid, a death agonist member of the Bcl-2 family, was processed by caspases following exposure of cells to NOC-18, supporting the above notion. Thus, NO-mediated apoptosis in HL-60 cells involves a caspase/cytochrome c-dependent mechanism.
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PMID:Caspase activation and cytochrome c release during HL-60 cell apoptosis induced by a nitric oxide donor. 1079 16

To define the responses of apoptotic regulatory proteins to different chemotherapeutic agents, we investigated the expression of Bcl-2 family gene products, the release of cytochrome c, and the activation of pro-caspase-3 during apoptosis induced by Taxol and Thiotepa, in the MCF-7 breast carcinoma and the HL-60 leukemia cell lines. The earliest event induced by drug exposure was increase in Bad protein levels, followed by Bcl-2 down-regulation, cytochrome c release, and Bcl-xL and Bax up-regulation. Bak accumulation was a late event. Activation of pro-caspase-3 and cleavage of Bcl-2 protein occurred in the HL-60 cells only, and followed the cytochrome c release. The overall responses were qualitatively similar in both cell types, but MCF-7 cells treated with Taxol showed a significant delay in apoptosis, correlating with early up-regulation of Bcl-2 and delayed release of cytochrome c. We conclude that Bad up-regulation is an early indicator of a cellular response that will lead to cell death, but may be modulated by survival mechanisms, which cumulatively govern the ultimate susceptibility to apoptosis.
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PMID:Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-xL protein levels. 1082 81


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