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 purpose of this study was to explore the effect of N, N'-di-(m-methylphenyi)-3, 6-dimethyl-1, 4-dihydro-1, 2, 4, 5-tetrazine-1, 4-dicarboamide (ZGDHu-1) on proliferation, differentiation and apoptosis in NB4 human leukemia cell line and its possible mechanism. Different concentrations of ZGDHu-1 and the different time of cultivation were used to treat NB4 cells. The proliferation inhibition of NB4 cells was analysed by cell counting, alive cell count, MTT assay. Cell apoptosis was determined by cell morphology, DNA agarose gel electrophoresis, DNA content, Annexin-V/PI and Hoechst 33258 labeling method. The analysis of cell morphological change, expression of CD11b, CD13 and NBT reduction were performed to evaluate the differentiation of NB4 cells. The expressions of bcl-2, bax and phosphorylated p38MAPK or STAT3 were detected by flow cytometry. While the expression of hTERT mRNA in transcriptional level was measured by fluorescence quantitative RT-PCR. The results showed that ZGDHu-1 could inhibit NB4 cell proliferation viability within a certain range of treating time and does, IC(50) values at 48 and 72 hours were 450 ng/ml and 200 ng/ml respectively. A majority of NB4 cells were arrested in G(2/M) phase and a progressive decline of cells was seen in G(0/1). The NB4 cells apoptosis was confirmed by cell typical cell morphology, DNA fragments and sub-G(1) phase peak as well as Hoechst33258 and Annexin-V/PI labeling method with a time-dose-related manner. The morphology of NB4 cells cultured in the presence of 2 - 100 ng/ml ZGDHu-1 for three days was more mature with higher NBT positivity and expressions of CD11b and CD13 than those in control. The expression of phosphor-p38MAPK and bax was increased while phosphor-STAT3 and bcl-2 were unchanged by the treatment of ZGDHu-1. ZGDHu-1 could decrease the expression of hTERT-mRNA in a dose-dependent manner. It is concluded that ZGDHu-1 can inhibit proliferation, induce differentiation and apoptosis of NB4 cells. The mechanism may be associated with up-regulation of bax expression, enhancement of phosphor-p38MAPK activation and inhibition of hTERT-mRNA.
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PMID:[Effects of N, N'-Di-(m-methylphenyi)-3, 6-dimethyl-1, 4-dihydro-1, 2, 4, 5-tetrazine-1, 4-dicarboamide on proliferation, apoptosis and differentiation of NB4 leukemia cells in vitro]. 1709 81

Matrine, a low toxic alkaloid purified from the Chinese herb Kushen, has been reported to induce apoptosis in leukemia K562 cells. In this study, the mechanism underling this apoptotic event was investigated. Treatment of K562 cells with matrine resulted in inhibition of cell survival more significantly than treatment of non-cancer fibroblast NIH3T3 cells. When K562 cells were incubated with matrine in higher than 0.2 mg/ml doses for 48 hours, the apoptotic cells were increased and both poly (ADP-ribose) polymerase (PARP) and caspase-3 were cleaved in a dose dependent manner. General caspase inhibitor (z-VAD-fmk) or caspase-3 inhibitor (z-DEVD-fmk) almost completely suppressed matrine-induced apoptosis. In addition, matrine increased proapoptotic protein bax and caused the release of cytochrome C. Taken together, the results suggest that matrine induces a cytochrome C-mediated, caspase-dependent apoptosis.
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PMID:Molecular mechanism of matrine-induced apoptosis in leukemia K562 cells. 1716 97

We hypothesized that studying protein expression in cells surviving in vitro chemotherapy ("survivor cells", SV), could provide more important insight into the biology of drug-resistant AML cells than analysis of the bulk population of leukemic cells. Leukemia-enriched samples from 79 patients with new or relapsed AML were cultured for four days +/- cytarabine (5-10 microM). Early apoptotic cells were removed to yield purified SV. Expression of BCL2, bax, PKC alpha, ERK2 and pERK2 proteins was measured using laser scanning cytometry. The SV population was enriched for CD34+ stem cells. Protein expression patterns in SV differed considerably from those in controls; culture and reanalysis of protein expression revealed stability, reversion, or new patterns of change. Patterns of pairs or triads of proteins were nonrandomly distributed and appeared at statistically unlikely frequencies, suggesting preferential adoption of certain patterns. The patterns of change were highly predictive of remission attainment, relapse, and survival in univariate and multivariate analysis. We conclude that in vitro SV cells have protein expression patterns distinct from those of the bulk population of leukemic cells and that these patterns are predictive of outcome. Analysis of SV cells may be more informative than analysis of the bulk population of leukemia cells.
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PMID:Studying the right cell in acute myelogenous leukemia: dynamic changes of apoptosis and signal transduction pathway protein expression in chemotherapy resistant ex-vivo selected "survivor cells". 1717 52

The aim of study was to investigate the mechanism of N, N'-di-(m-methylphenyl)-3, 6-dimethyl-1, 4-dihydro-1, 2, 4, 5-tetrazine-1, 4-dicarboamide (ZGDHu-1) inducing apoptosis in SHI-1 human leukemia cell line. Different concentrations of ZGDHu-1 and different times of culture were used to treat SHI-1 cells; the apoptosis of SHI-1 cells was analyzed by morphology, DNA agarose gel electrophoresis, DNA content detection, Annexin-V/PI and Hoechst33258 labeling method, the mitochondrial transmembrane potential (Delta Psi m) were measured by dihydrorhodamin 123, and expressions of bcl-2, bax, Fas, p53 and mitochondrial membrane protein were analyzed by flow cytometry, while the bcl-2, bax and p53 gene were analyzed by RT-PCR. The transcriptional level of hTERT-mRNA was measured by real-time fluorescence quantitative RT-PCR. The results showed that after exposure to ZGDHu-1, SHI-1 cells were induced to apoptosis in a time-and does-dependent manner. SHI-1 cell apoptosis was confirmed by typical cell morphology, DNA fragmentation, sub-G(1) phase, Hoechst33258 and Annexin-V/PI labeling etc. The expression of bax, bax/bcl-2, p53 and Fas gene significantly increased and bcl-2 slightly decreased. ZGDHu-1 could increased the expression of mitochondrial membrane protein in a dose-dependent manner while Delta Psi m reduced. The expression of hTERT-mRNA significantly decreased. It is concluded that ZGDHu-1 can up-regulate the expression of p53, bax and bax/bcl-2. The mitochondrial pathway mediated by descent of mitochondrial transmembrane potential may be one of the mechanisms inducing apoptosis by ZGDHu-1, in which Fas gene also participates. Telomerase may be an effective gene target for anti-tumour effect of ZGDHu-1.
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PMID:[ZGDHu-1-inducing apoptosis of SHI-1 leukemia cells and its molecular mechanism]. 1760 50

Increasing evidence suggests that aberrant activation of PI3K/Akt is involved in many human cancers, and that inhibition of the PI3K/Akt pathway might be a promising strategy for cancer treatment. Our investigation indicates that Rhabdastrellic acid-A, an isomalabaricane triterpenoid isolated from the sponge, Rhabdastrella globostellata, inhibits proliferation of HL-60 cells with an IC(50) value of 0.68mug/ml, and induces apoptosis. Rhabdastrellic acid-A also induces cleavage of the death substrate poly (ADP-ribose) polymerase (PARP) and caspase-3. Pretreatment of HL-60 cells with the caspase-3 specific inhibitor, DEVD-CHO, prevents Rhabdastrellic acid-A-induced DNA fragmentation and PARP cleavage. Activated PI3K and Akt significantly decreases after treatment with Rhabdastrellic acid-A in HL-60 cells. Expression levels of protein bcl-2, bax remain unchanged in response to Rhabdastrellic acid-A treatment in HL-60 cells. These results suggest that Rhabdastrellic acid-A inhibits PI3K/Akt pathway and induces caspase-3 dependent-apoptosis in HL-60 human leukemia cells.
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PMID:Rhabdastrellic acid-A inhibited PI3K/Akt pathway and induced apoptosis in human leukemia HL-60 cells. 1792 Mar 3

Apoptosis plays a key role in the control of rapidly renewing tissues, such as the hematopoietic system and leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells and the development of drug resistance. These defects are also frequently associated with a low rate of response to standard chemotherapy and with a poor survival in acute myeloid leukemia (AML). The major form of apoptosis proceeds through the mitochondrial pathway, with the mitochondrial outer membrane permeabilization, leading to the release of proteins normally found in the space between the inner and outer mitochondrial membranes (cytochrome C, AIF and others). Higher levels of anti-apoptosis proteins bcl-2, bcl-x(L), Mcl-1 block permeabilization of the membrane and are reported in AML patients presenting a poor outcome. On the contrary, activated pro-apoptotic bax or bad proteins allow this permeabilization and are correlated to a good prognosis in AML. Defects in the mitochondrial pathway induce multidrug-resistance and confer important prognostic information in AML. High ratios of bcl-2 to bax protein confer a poor prognosis with decreased rates of complete remission and overall survival. The prognostic information from the ratio of the proteins is greater than bcl-2 levels alone. Recently, we confirmed the impressive impact of the bax/bcl-2 ratio, determined by flow cytometry, on AML prognosis (complete remission and overall survival) in 255 AML patients. Bcl-2 down regulation might lower the apoptotic threshold of leukemic cells and, through this mechanism, favor response to chemotherapy. Phase II studies of oblimersen (antisense Bcl-2), cytarabine and daunorubicin or oblimersen plus gentuzumab, a cytotoxic antibody directed against CD33+ cells in relapsed AMLs, showed promising results. Defects in apoptosome proteins, such as APAF-1, are frequent in AML and treatment with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored APAF-1 expression in leukemic cells. In conclusion, targeted therapies that are designed to induce apoptosis in leukemic cells, are the most promising anti-leukemia strategies. The elucidation of the apoptotic machinery and of its defects in AML lays the basis for developing new drugs able to trigger apoptosis and overcome therapy resistance.
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PMID:Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. 1847 34

Puma (p53 upregulated modulator of apoptosis) belongs to the BH3 (Bcl-2 homology 3)-only protein family of apoptotic regulators. Its expression is induced by various apoptotic stimuli, including irradiation and cytokine withdrawal. Using an inducible system to express Puma, we investigated the nature of Puma-induced apoptosis. In BaF(3) cells, expression of Puma caused rapid caspase-mediated cleavage of ICAD (inhibitor of caspase-activated deoxyribonuclease) and Mcl-1 (myeloid cell leukemia 1), leading to complete loss of cell viability. Surprisingly, Puma protein levels peaked within 2 h of its induction and subsequently declined to basal levels. Maximal Puma abundance coincided with the onset of caspase activity. Subsequent loss of Puma was prevented by the inhibition of caspases, indicating that its degradation was caspase dependent. In cells expressing transfected Bcl-2, induced Puma reached significantly higher levels, but after a delay, caspases became active and cell death occurred. Puma co-immunoprecipitated endogenous Bcl-2 and Mcl-1 but not Bax and Bak, suggesting that Puma did not associate with either Bax or Bak in these cells to initiate cell death. In mouse embryonic fibroblasts (MEFs), the amount of Puma peaked within 4 h of its induction. In contrast, in bax/bak double-knockout MEFs, Puma was stably expressed following its induction and was unable to trigger apoptosis even at very high levels. Overexpression of Bcl-2 in wild-type MEFs, like in BaF(3) cells, resulted in higher levels of Puma being reached but did not prevent cell death from occurring. These results demonstrate that the level of the Bcl-2 prosurvival family sets the threshold at which Puma is able to indirectly activate Bax or Bak, leading in turn to activation of caspases that not only cause cell death but also rapidly induce Puma degradation.
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PMID:Triggering of apoptosis by Puma is determined by the threshold set by prosurvival Bcl-2 family proteins. 1883 64

This study was aimed to explore the apoptotic effect of Resveratrol (RES) on KG-1 cells and the expression of bcl-2/bax in vitro, and to clarify the possible mechanism of apoptotic effect of RES on leukemia cells. After treating with different concentrations of RES, the suppressive effect of RES on proliferation of KG-1 cells was analyzed by MTT method. Transmission electron microscope technique were used to detect the apoptosis status of KG-1 cells. The cell cycle and apoptosis percentage of KG-1 cells treated with RES were detected by flow cytometry. The expressions of bcl-2, bax mRNA and protein were assessed by semiquantitative RT-PCR and flow cytometry. The results showed that RES could obviously inhibit proliferation of KG-1 cells (p < 0.05). Compared with the control group, the cell number in S phase of KG-1 cells treated with RES increased (p < 0.05), the apoptosis rate enhanced significantly (p < 0.01) and the expression level was down-regulated, while expression level of bax was obviously up-regulated (p < 0.01). It is concluded that RES significantly induces apoptosis of KG-1 cells in vitro, which is probably related to the down-regulation of bcl-2 expression and up-regulation of bax expression.
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PMID:[Relationship between apoptotic effect of Resveratrol on KG-1 cells and expression of bcl-2/bax]. 1892 88

In India, arsenic contamination in ground water is of immediate environmental concern affecting a large number of inhabitants in Kolkata. Arsenic is known to be one of the most toxic metalloids naturally occurring in the environment giving rise to severe toxic manifestations including cancer. Because arsenic is also used in chemotherapy of leukemia, it was considered worthwhile to concentrate on the mechanism of toxic action in normal hepatocytes which has not been addressed earlier. Rat hepatocytes were isolated and incubated in As(2)O(3) at concentrations of 10, 20, and 40 microM in a time-dependent manner (0, 15, 30 min and 1, 2, and 4 h). The expression of the common stress proteins HSP 70 and 90 throughout the experimental duration confirmed the magnitude of toxic effect imposed by arsenic. Microscopic observations showed clear apoptotic changes in hepatocytes, which were further characterized by DNA ladder formation in time- and concentration-dependent manners. Apoptosis was triggered by caspase activation and over expression of bax at 10 microM As(2)O(3) and at 20 and 40 microM concentrations of As(2)O(3), MAP kinases were found to mediate the apoptotic pathway. Co-treatment of cells with arsenic and caspase inhibitor (Ac-DEVD-Cho) led to over expression of bcl-2, suppression of bax, and cytosolic sequestration of Bid and Bad. It is therefore concluded that caspase activation has a direct role in arsenic-induced apoptosis mediated by mitochondrial factors at 10 microM As(2)O(3), and JUN N-terminal kinase (JNK) and P38 activation are the major mediators of apoptosis at the higher test concentrations (20 and 40 microM) of As(2)O(3).
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PMID:As2O3 toxicity in rat hepatocytes: manifestation of caspase-mediated apoptosis. 1914 69

The src homology 2 (SH2)-domain containing inositol-5-phosphatase (SHIP) is another recently identified lipid phosphatase after phosphatase and tensin homology deleted on chromosome ten gene (PTEN). It plays an important role in negatively regulating the proliferation of hematopoietic cells. The relationship between SHIP and the inhibition of tumor proliferation is rarely reported. The purpose of this study is to evaluate the apoptosis induced by SHIP gene in K562 cell line and to explore the involved signaling pathway. The K562 cells were transfected with human SHIP gene by using the lentiviral vector containing SHIP, and the transfection was verified by fluorescent quantitative PCR (FQ-PCR) and Western blot. Then the effects of SHIP protein expression on cell growth and apoptosis were measured. The levels of p-Akt, bcl-2 family, caspase and the activity of NFkappaB were assayed by Western blot and ELISA, respectively. The results are as follows: (1) Human leukemia cell line K562 was SHIP-negative; (2) Transfection with SHIP gene led to the re-expression of SHIP mRNA and protein in K562, as shown by FQ-PCR and Western blot; (3) The expression of SHIP protein inhibited cell growth and significantly increased apoptosis in K562 cells; (4) Compared to that in control group, the expression level of p-Akt-308 and p-Akt-473 in SHIP-expressing cell group decreased significantly (P<0.01); SHIP activated caspase-9, caspase-3, up-regulated protein levels of bad, p27, down-regulated expression of bcl-xL, while it had no effect on the expression of bcl-2 and bax. Furthermore, the inhibition of NF-kappaB was achieved along with the inactivation of Akt. These data suggest that SHIP gene has potential abilities to inhibit K562 leukemic cell proliferation and induce its apoptosis via inactivating PI3K/Akt pathway. The loss of SHIP might be the explanation of aberrant high-level p-Akt in human leukemia. It may be at least one of the mechanisms by which the loss of SHIP expression contributes to leukemia progression.
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PMID:[The mechanism for SHIP gene to induce the apoptosis of human leukemia cell line K562.]. 1937 26


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