Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The demethylating effect of 5-Aza-CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition. Here, 5-Aza-CdR induced apoptosis in AML cells (both p53 mutant and wild-type) but not in epithelial or normal PBMCs. Cell death was accompanied by activation of the mitochondrial apoptosis pathway, as shown by release of cytochrome c and AIF and loss of mitochondrial membrane potential (DeltaPsim). Activation of caspase-3 (but not -6 and -8) was detectable using Western blot analysis and measurement of caspase enzymatic activity. 5-Aza-CdR treatment resulted in the induction of p21, which correlated with the arrest of AML cells in the G1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but mediated by 5-Aza-CdR-induced reexpression of the tumor-suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells, which were resistant toward 5-Aza-CdR. Therefore, 5-Aza-CdR-mediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5-Aza-CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation-dependent efficacy of 5-Aza-CdR in AML cells.
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PMID:5-Aza-2'-deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. 1560 9

Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl(+) human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34(+) cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of Bcr-Abl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and B-Raf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl(+) leukemias, including those resistant to STI571.
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PMID:Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change. 1562 78

We compare the effects of Imatinib mesylate (Glivec) on chronic myeloid leukemia derived cell lines K562 and JURL-MK1. In both cell lines, the cell cycle arrests in G(1)/G(0) phase within 24 h after the addition of 1 microM Imatinib. This is followed by a decrease of Ki-67 expression and the induction of apoptosis. In JURL-MK1 cells, the apoptosis is faster in comparison with K562 cells: the caspase-3 activity reaches the peak value (20 to 30 fold of the control) after about 40 h and the apoptosis proceeds to its culmination point, the DNA fragmentation, within 48 h following 1 microM Imatinib addition. Unlike K562 cells, JURL-MK1 cells possess a probably functional p53 protein inducible by TPA (tetradecanoyl phorbol acetate) or UV-B irradiation. However, no increase in p53 expression was observed in Imatinib-treated JURL-MK1 cells indicating that the difference in the apoptosis rate between the two cell lines is not due to the lack of p53 in K562 cells. Imatinib also triggers erythroid differentiation both in JURL-MK1 and K562 cells. Glycophorin A expression occurred simultaneously with the apoptosis, even at the single cell level. In K562 cells, but not in JURL-MK1 cells, the differentiation process involved increased hemoglobin synthesis. However, during spontaneous evolution of JURL-MK1 cells in culture, the effects produced by Imatinib progressively changed from the fast apoptosis to the more complete erythroid differentiation. We suggest that the apoptosis and the erythroid differentiation are parallel effects of Imatinib and their relative contributions, kinetics and completeness are related to the differentiation stage of the treated cells.
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PMID:Fast apoptosis and erythroid differentiation induced by imatinib mesylate in JURL-MK1 cells. 1577 Jun 64

Mitochondria play a key role in the regulation of apoptosis induced by numerous antitumor chemotherapeutic and other toxic agents. Photodynamic therapy (PDT) exerts significant cellular killing efficacy through either an apoptotic or necrotic cell death pathway. This study investigated the mechanism underlying the killing effects of a novel amphipathic photosensitizer [di-sulfonated di-phthalimidomethyl phthalocyanine zinc (ZnPcS2P2)]-mediated photodynamic therapy (ZnPcS2P2-PDT) on K562 cells. Apoptosis was evident in the post-PDT cells through the TdT-mediated dUTP nick end labeling (TUNEL) method and DNA fragmentation assay. After ZnPcS2P2-PDT, K562 cells underwent mitochondria-dependent apoptosis as evidenced by the release of cytochrome c from mitochondria into cytosol, accompanied by mitochondrial membrane potential (deltapsim) reduction, indicating the opening of the mitochondrial permeability transition pore (PTP). The activities of protease from the caspase family and caspase-3 were also significantly elevated. Furthermore, ZnPcS2P2-PDT down-regulated the expression of chimaeric Bcr-Abl oncoprotein, which is the molecular hallmark of chronic myelogenous leukemia (CML).
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PMID:ZnPcS2P2-based photodynamic therapy induces mitochondria-dependent apoptosis in K562 cells. 1599 10

Gleevec, which is an inhibitor of the bcr/abl tyrosine kinase, has been a remarkable success for the treatment of chronic myelogenous leukemia (CML). However, a significant proportion of patients chronically treated with Gleevec develop resistance. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevec-sensitive and -resistant Ph+ CML cells. The IC50 values of berbamine were 8.80 microg/ml in Gleevec-sensitive Ph+ CML cells, 11.34 microg/ml in Gleevec-resistant Ph+ CML cells, and 54.40 microg/ml in Ph- KG-1 cells, respectively. Similarly, berbamine was also found to display a selective anti-proliferative activity of primary leukemia cells from CML patients, and its IC50 values were 4.20-10.50 microg/ml in primary CML cells, and 185.20 microg/ml in normal bone marrow cells, respectively. More importantly, our studies demonstrate that berbamine down-regulates p210bcr/abl oncoprotein level, and induces apoptosis of bcr/abl+ cells through caspase-3-dependent pathway. These data suggest that berbamine might be a novel bcr/abl inhibitor with potent anti-leukemia activity.
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PMID:Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. 1602 22

To explore the effects of vascular endothelial growth factor (VEGF) on the mechanisms of CML pathogenesis, the effect of VEGF on K562 cell apoptosis induced by As(2)O(3) was analyzed through morphologic observation, DNA fragmentation agarose gel electrophoresis and DNA ploidy flow cytometry analysis, and the effect of VEGF on the expression of bcl-X(L), Bax and caspase-3 in K562 cells was determined by Western blot, meanwhile the expression difference between bcl-X(L) and Bax mRNA in above conditions was detected by RT-PCR. The results showed that after VEGF added, the apoptosis of K562 cells reduced, however, there was no significant changes in cell cycle distribution (P > 0.05). At the same time, following the increasing of the concentration of VEGF, expression of mRNA and protein of bcl-X(L) was up-regulated and the expression of Bax protein was down-regulated in K562 cells, and the activation of pro-caspase-3 into caspase-3 was inhibited or reduced. It is concluded that VEGF may suppress the apoptosis of K562 cells through its influence on the bcl-X(L)/Bax expression ratio in K562 cells.
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PMID:[Anti-apoptosis effect of VEGF on the human chronic myelocytic leukemia cell line K562]. 1627 41

Tumors generally display a high glycolytic rate. One consequence of increased glycolysis is the non-enzymatic glycation of proteins leading to the formation of advanced glycation end-products (AGEs). Therefore, we studied the presence of AGEs in non-small cell lung cancer and consequences thereof. We show the presence of two AGEs, i.e. the major AGE N(epsilon)-(carboxymethyl)lysine (CML) and the methylglyoxal-arginine adduct argpyrimidine, in human non-small cell lung cancer tissues by immunohistochemistry. We found in squamous cell carcinoma and adenocarcinoma tissues a strong CML positivity in both tumour cells and tumour-surrounding stroma. In contrast, argpyrimidine positivity was predominantly found in tumor cells and was strong in squamous cell carcinomas, but only weak in adenocarcinomas (2.6+/-0.5 vs. 1.2+/-0.4, respectively; P<0.005). In accordance, argpyrimidine was found in the human lung squamous carcinoma cell line SW1573, while it was almost absent in the adenocarcinoma cell line H460. Heat shock protein 27 (Hsp27) was identified as a major argpyrimidine-modified protein. In agreement with a previously described anti-apoptotic activity of argpyrimidine-modified Hsp27, the percentage of active caspase-3 positive tumor cells in squamous cell carcinomas was significantly lower when compared to adenocarcinomas. In addition, incubation with cisplatin induced almost no caspase-3 activation in SW1573 cells while a strong activation was seen in H460 cells; which was significantly reduced by incubation with an inhibitor of glyoxalase I, the enzyme that catalyzes the conversion of methylglyoxal. These findings suggest that a high level of argpyrimidine-modified Hsp27 is a mechanism of cancer cells for evasion of apoptosis.
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PMID:Argpyrimidine-modified Heat shock protein 27 in human non-small cell lung cancer: a possible mechanism for evasion of apoptosis. 1633 38

The effects of a novel kind of nitrogen heterocycle compound, which was synthesized in our laboratory previously, on human chronic myelogenous leukemia K562 cells were investigated. The morphological changes were observed by Acridine orange (AO) staining. The screened results through DNA fragmentation and the Annexin V-FITC/PI staining assay showed that compound 8 blocked cell cycles at G(1) phase which led to apoptosis. The increase of caspase-3, 8, and 9 was detected, indicating that both of death-receptor and mitochondria-pathways were activated. Compound 8 induced a biphasic alteration in mitochondrial membrane potential of K562 cells. A dramatic elevation of Ca(2+) was also observed. In addition, a transient increase of ROS was also involved in the process. This study showed that compound 8 might be a potential chemopreventive agent for chronic myelogenous leukemia. It would guide our future work to synthesize more compounds derived from compound 8, which might have better effect, and to determine the target protein. Moreover, it might also provide a background mechanism for the introduction of this new type of promising therapeutic agent.
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PMID:A novel kind of nitrogen heterocycle compound induces apoptosis of human chronic myelogenous leukemia K562 cells. 1646 24

Previous studies reported that the neurotoxin, Crotoxin, isolated from the venom of South American rattlesnake had potent anti-tumor activity. Here, we investigated the involvement of autophagy and apoptosis in the Crotoxin-induced death of chronic myeloid leukemia cell line K562 cells. The neurotoxin dose dependently inhibited the viability of K562 cells. Crotoxin stimulated the autophagic activity as evidenced by the appearance of punctuate monodansylcadaverine (MDC) fluorescence staining in the cytoplasm and increased the formation of autophagosomes. Crotoxin caused the collapse of the mitochondrial membrane potential, release of cytochrome c and activation of caspase-3. Caspase inhibitors attenuated Crotoxin-induced K562 cell death, while blockage of autophagy maturation with 3-methyladenine (3-MA) and NH4Cl potentiated the neurotoxin's cytotoxicity. These results suggest that an apoptotic mechanism contributes to the Crotoxin-induced death of K562 cells, while the activation of autophagy delays neurotoxin-induced apoptosis.
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PMID:Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. 1654 94

Celecoxib, a specific cyclooxygenase-2 (Cox-2) inhibitor, has been shown to possess antitumor activity in a variety of cancer cells. However, the antitumor activity of celecoxib in hematopoietic tumors, especially in chronic myeloid leukemia (CML), has not been well established. This study was designed to investigate the effect of celecoxib on growth and apoptosis in a human CML cell line (K562 cells) or in primary CML cells, and to examine the synergistic actions of celecoxib and hydroxyurea or imatinib on K562 cell proliferation and apoptosis. Celecoxib significantly inhibited the growth of both K562 and primary CML cells and induced apoptosis in a dose-dependent fashion. The IC50 of celecoxib was 46 microM for inhibition of K562 cell proliferation. The effect of celecoxib on growth inhibition was accompanied by the downregulation of cyclin D1 and cyclin E and p-Rb expression, the upregulation of P16(INK4a) and P27KIP expression, and a G1-S phase arrest of the cell cycle. The pro-apoptotic effect of celecoxib was determined to be mediated by caspase-3 activation. When K562 cells were pretreated with DEVD-fmk, a specific inhibitor of caspases, the apoptotic activity of celecoxib was, in part, abrogated. Importantly, we demonstrated for the first time that K562 cells were Cox-2-positive both at the mRNA and protein levels. We noted the following observations: (i) we detected Cox-2 mRNA in K562 cells by reverse transcription-PCR (RT-PCR) and protein expression by western blot analysis; (ii) Cox-2 expression in K562 cells was stimulated by IL-1beta, a specific inducing agent of Cox-2 expression; (iii) primary CML cells from CML patient bone marrow also exhibited Cox-2 protein expression. Furthermore, Cox-2 expression was downregulated at higher doses of celecoxib (80-160 microM), suggesting a Cox-2-dependent mechanism was involved in the drug's effects of growth inhibition and induction of apoptosis. In addition, a synergistic effect was observed when cells were exposed to low-dose celecoxib (40 microM) and hydroxyurea (10 mM) or a combination of celecoxib (40 microM) and imatinib (0.2 microM). These findings provide the basis for uncovering the mechanism of celecoxib's antitumor effects and developing a new therapeutic strategy for treating CML.
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PMID:Antitumor effects of celecoxib on K562 leukemia cells are mediated by cell-cycle arrest, caspase-3 activation, and downregulation of Cox-2 expression and are synergistic with hydroxyurea or imatinib. 1655 May 20


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