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)

In the present study, we investigated the in vitro apoptotic response of leukemic cells to the cellular stress induced by homoharringtonine (HHT), a plant alkaloid with antileukemic activity which is currently being tested for treatment of acute and chronic leukemias. A comparison of leukemic cell lines with different p53 gene status revealed a considerably higher sensitivity to HHT-induced apoptosis in the cells with a wt p53, and apoptotic events in wt p53 leukemia cells (MOLT-3 cell line) were studied in more detail. To this end, we examined components of apoptotic cascades including Bax expression and its intracellular localization, changes of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, cytochrome c release from mitochondria and activation of caspases. Bax protein levels did not increase despite an up-regulation of bax at mRNA level. However, Bax translocation from cytosol towards mitochondria was observed. In addition, we observed a release of cytochrome c from the mitochondria, and the localization changes of both Bax and cytochrome c were found already at the early, annexin V-negative stage of HHT-induced apoptosis. HHT-treated MOLT-3 cells revealed loss of MMP as well as activation of caspases demonstrated by DEVD-, IETD- and LEHD-tetrapeptide cleavage activity in the cell lysates. ROS levels only slightly increased in HHT-treated cells and antioxidants did not prevent apoptosis and MMP changes. Therefore, wt p53 leukemic cells respond to HHT-specific cellular stress by induction of ROS-independent apoptotic pathway characterized by translocation of Bax, mitochondrial cytochrome c release and activation of caspases.
Leukemia 2001 Apr
PMID:Apoptotic response to homoharringtonine in human wt p53 leukemic cells is independent of reactive oxygen species generation and implicates Bax translocation, mitochondrial cytochrome c release and caspase activation. 1136 58

Seven structurally related flavonoids including luteolin, nobiletin, wogonin, baicalein, apigenin, myricetin and fisetin were used to study their biological activities on the human leukemia cell line, HL-60. On MTT assay, wogonin, baicalein, apigenin, myricetin and fisetin showed obvious cytotoxic effects on HL-60 cells, with wogonin and fisetin being the most-potent apoptotic inducers among them. The cytotoxic effects of wogonin and fisetin were accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including DNA fragmentation, apoptotic bodies and the sub-G1 ratio. Treatment with an apoptosis-inducing concentration of wogonin or fisetin causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity. Further, cleavage of poly(ADP-ribose) polymerase (PARP) and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated HL-60 cells. An increase in the pro-apoptotic protein, bax, and a decrease in the anti-apoptotic protein, Mcl-1, were detected in fisetin- and wogonin-treated HL-60 cells. However, Bcl-2, Bcl-XL, and Bad all remained unchanged in wogonin- and fisetin-treated HL-60 cells. In vitro chromatin digestion revealed that endonuclease activity was profoundly enhanced in wogonin- and fisetin-treated HL-60 cells, and the addition of ethylenediaminetetraacetic acid (EDTA) or ethyleneglycoltetraacetic acid (EGTA) into the reaction blocked endonuclease activation and at an optimum pH of 7.5. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated wogonin- and fisetin-induced DNA ladders, PARP cleavage, and endonuclease activation. Pretreatment of HL-60 cells with N-acetyl-cysteine or catalase efficiently inhibited H(2)O(2) (200 microM)-induced apoptosis, but showed no inhibitory effect on wogonin- and fisetin-induced DNA ladders, caspase 3 activation, or bax protein induction. Decrease in endogenous ROS production was detected in wogonin- and fisetin-treated HL-60 cells by DCHF-DA assay. In conclusion, our experiments indicate that a decrease in intracellular peroxide level was involved in wogonin- and fisetin-induced apoptosis; activation of caspase 3 and endonuclease, induction of bax protein and suppression of Mcl-1 protein were detected in the process.
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PMID:Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease. 1184 97

Glucosinolates (GL) can inhibit, retard or reverse experimental multistage carcinogenesis. When brassica plant tissue is broken, GLs are hydrolyzed by the endogenous enzyme myrosinase (Myr), releasing many products including isothiocyanates (ITC). Synthetic ITCs like sulforaphane exert chemopreventive effects against chemically induced tumors in animals, modulating enzymes required for carcinogens' activation/detoxification and/or the induction of cell-cycle arrest and apoptosis in tumor cell lines. To investigate the chemopreventive potential of ITCs while reproducing the circumstances of dietary contact with sulforaphane, we studied proliferation, apoptosis induction and p53, bcl-2 and bax protein expression in Jurkat T-leukemia cells by sulforaphane, the ITC generated in situ in a quantitative manner by Myr starting from glucoraphanin (GRA). Jurkat cells were treated with different doses of GRA-Myr mixture. Effects on cell growth or survival were evaluated by counting trypan blue-excluding cells. Cell-cycle progression, apoptosis and expression of p53, bax and bcl-2 proteins were analyzed by flow cytometry. Results were analyzed by two-sided Fisher's exact test. Sulforaphane, but not GRA, caused G(2)/M-phase arrest (P = 0.028) and increase of apoptotic cell fraction (P < 0.0001) in a time- and dose-dependent manner. Necrosis was observed after prolonged exposure to elevated sulforaphane doses. Moreover, it markedly increased p53 and bax protein expression, and slightly affected bcl-2 expression. These findings indicate that sulforaphane but not the native GL GRA can exert both protective and toxic effects inhibiting leukemic cell growth. Sulforaphane therefore deserves study as a potential chemopreventive/chemotherapeutic antileukemic agent.
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PMID:Growth inhibition, cell-cycle arrest and apoptosis in human T-cell leukemia by the isothiocyanate sulforaphane. 1196 Sep 9

In B-CLL, non-proliferating B cells accumulate due to defective apoptosis. Cytotoxic therapies trigger apoptosis and deregulation of apoptotic pathways contributes to chemoresistance. Loss of the apoptosis-promoting Bax has been implicated in resistance to cytotoxic therapy. We therefore evaluated ex vivo drug sensitivity of CLL, producing chemoresponse data which are prognostic indicators for B-CLL, in particular in the case of purine nucleoside analogs. To analyze the underlying mechanisms of drug resistance, we compared endogenous Bax and Bcl-2 expression to ex vivo response to eight drugs, and to survival in 39 B-CLL patients. We found that reduced Bax levels correlated well with ex vivo resistance to traditional B-CLL therapies - anthracyclines, alkylating agents and vincristine (all P < 0.04). Surprisingly, no such relationship was observed for the purine nucleoside analogs or corticosteroids (all P > 0.5). Mutational analysis of p53 could not explain the loss of Bax protein expression. Levels of Bcl-2 were not associated with sensitivity to any drug. In contrast to the ex vivo data, neither Bax or Bcl-2 expression nor doxorubicin sensitivity were associated with increased survival whereas sensitivity to fludarabine correlated with better overall survival (P = 0.031). These findings suggest that the resistance to purine nucleoside analogs and corticosteroids in B-CLL is due to inactivation of pathways different from those activated by anthracyclines, vinca alkaloids and alkylating agents and may be the molecular rationale for the efficacy of purine analogs in this disease.
Leukemia 2002 Jun
PMID:Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia. 1204 Apr 35

The use of topoisomerase inhibitors has been associated with the development of secondary malignancies, suggesting that these agents can induce DNA damage that may be persistent. We have investigated the effect of short exposures (>3 days) to low etoposide concentrations (LC-etoposide, 0.01-0.04 microM) on the ability of leukaemic cells to initiate apoptosis. Results showed that although LC-etoposide had no effect on cell growth characteristics, the pre-culture of cells with LC-etoposide conferred resistance to subsequent exposure to cytotoxic concentrations of etoposide (0.3 microM etoposide in HL60 on day 3: %V: 95.2 +/- 1.6% vs 60.3 +/- 12.1% in control cells with no pre-culture, and %A: 5.1 +/- 0.2 vs 19.0 +/- 0.7%; P < 0.001). This effect was still observed 4 weeks after the initial drug exposure. Associated with these observations was a three-fold increase in genetic instability and a reduction in induced bax protein levels. The anti-cytotoxic effect was also shown to be specific to topoisomerase II (topo II) inhibitors, as the pre-culture of cells with a low doxorubicin concentration also induced resistance, while low cisplatin concentrations did not. The persistence of these alterations in cellular processes following an initial exposure to topo II inhibitors suggests a DNA-based mechanism, and highlights the existence of drug/target interactions even at very low drug concentrations.
Leukemia 2002 Sep
PMID:Exposure to low concentrations of etoposide reduces the apoptotic capability of leukaemic cell lines. 1220 Jun 85

Bendamustine is a novel cytostatic agent, with activity in non-Hodgkin's lymphomas including B-chronic lymphocytic leukemia (B-CLL). The knowledge about its mode of action, however, is still limited. Here, we investigated the in vitro ability of bendamustine to induce apoptosis on freshly isolated peripheral lymphocytes in B-CLL and analyze the potential underlying mechanisms of action for inducing apoptosis. In CLL cells taken from 37 previously treated and untreated CLL patients, we investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level using the RNase protection assay or flow cytometry, respectively. Apoptotic cells were determined with flow cytometry using the fluorescent DNA-binding agent 7-ADD. Using bendamustine alone in concentrations from 1 microg/ml to 50 microg/ml, a dose- and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 h could be observed. The LD50 for untreated and pretreated CLL cells was 7.3 or 4.4 microg/ml, respectively. The median apoptotic rate was similar in both groups. The combination of bendamustine with fludarabine led to a highly synergistic effect in inducing apoptosis, which was 150% higher than expected for bendamustine plus fludarabine. The level of the initial Bcl-2 and Bax protein and the m-RNA expression remained unchanged during the incubation with bendamustine. In conclusion, this study demonstrates for the first time the in vitro efficacy of bendamustine in inducing apoptosis in B-CLL cells alone and in combination with fludarabine.
Leukemia 2002 Oct
PMID:In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia. 1235 63

Glucocorticoid resistance is often associated with treatment failure in children with acute lymphoblastic leukaemia (ALL) but the underlying molecular mechanisms are still unclear. In 30 consecutive children with ALL treated with prednisone we determined changes in the expression of Bcl-2, Bax and Bcl-xl proteins in leukemic lymphoblasts and related these to clinical features and rate of prednisone-induced apoptosis. The apoptotic index increased after prednisone therapy in 24 of the 30 patients. At diagnosis, we detected expression of Bcl-2 and Bcl-xl protein in 28 samples, while Bax expression protein was detected in 21 of the 30 patients. Prednisone treatment induced a decrease in Bcl-2 and Bcl-xl levels in 17 and 16 of the 28 patients, respectively, while Bax protein increased in 14 of the 21 patients. Twenty of the 30 patients studied were considered to be good prednisone responders, whereas 10 were poor responders. We observed a statistically significant decrease only for Bcl-xl protein expression in T phenotype ALL, in the poor responder group and in patients with >20000/mm(3) white cell count (WBC) at diagnosis. These data suggest a role of Bcl-xl in the mechanisms of protection of leukemic cells from apoptosis induced by glucocorticoids (GCs).
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PMID:Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia. 1246 94

Despite experimental evidence that sulforaphane can exert chemopreventive effects, whether these effects are specific for neoplastic cells is not known. Following our previous demonstration that sulforaphane induces cell cycle arrest and apoptosis in human T lymphoblastoid Jurkat leukemia cells and increases p53 and bax protein expression, we tested sulforaphane on non-transformed phytohemagglutinin-stimulated human lymphocytes. Here, we demonstrate that sulforaphane arrested cell cycle progression in G, phase, through a decrease in the protein expression of cyclin D3. Moreover, sulforaphane induced apoptosis (and also necrosis), mediated by an increase in the expression of p53. These findings suggest that sulforaphane is a growth modulator for T cells. Our in vitro evidence that sulforaphane is active and even cytotoxic in normal as well as transformed lymphocytes raises important questions regarding its suitability for cancer chemoprevention.
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PMID:Cyclin D3 and p53 mediate sulforaphane-induced cell cycle delay and apoptosis in non-transformed human T lymphocytes. 1253 May 31

F 11782 (2",3"-bis-pentafluorophenoxyacetyl-4",6"ethylidene-beta-D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin-2N-methyl glucamine salt), is a novel dual catalytic inhibitor of topoisomerases I and II characterised by marked in vivo antitumour activity, which also proved cytotoxic and exhibited DNA damaging properties in vitro. Mechanisms associated with this cell killing by F 11782 have been examined in P388 leukaemia cells. Treatment with F 11782 resulted in a dose-dependent DNA fragmentation coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of F 11782 induced caspases-3/7 activation accompanied by proteolytic cleavage of poly(ADP-ribose)-polymerase, which could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. In addition, F 11782-induced apoptosis in P388 cells was associated with an increased expression of the pro-apototic Bax protein, without significant changes in the level of the anti-apoptotic Bcl-2 protein, and with modification at the mitochondrial membrane function. These results indicate that F 11782 leads to apoptosis through a caspase-3/7 dependent mechanism and suggest that the so-called "mitochondrial pathway" is implicated in F 11782-induced apoptosis in P388 cells.
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PMID:Apoptotic cell death induction by F 11782 a novel dual catalytic inhibitor of topoisomerases I and II. 1262 89

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


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