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)

Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells (Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations > or =0.75 microM for intervals > or =6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2- and CDK4-specific sites, as well as the caspase-dependent downregulation of cyclin D1. Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated (myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process.
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PMID:Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. 1464 18

Blockade of mitogen-activated protein kinase kinase (MEK1/2), part of the extracellular signal-regulated kinase (ERK) or p44/42 mitogen-activated protein kinase (MAPK) pathway has been shown, in some instances, to cause apoptosis in leukemic blast cells. However, studies are contradictory and have often been based mainly on inhibition of cell growth in a limited number of cell lines. This investigation examined the effect of the potent MEK inhibitor U0126 alone and in combination with Ara-C on apoptosis in acute myeloblastic leukemia (AML) cell lines, patient acute leukemic and nonleukemic samples. Apoptosis was assessed flow cytometrically using Apo2.7 and AnnexinV antibodies which detect apoptosis at the mitochondrial and cell membrane levels, respectively. The proapoptotic effect of the inhibitor varied across the five cell lines tested, from highly significant induction of apoptosis to no apparent response. A possible synergistic effect with the combined use of U0126 and Ara-C was observed in one cell line only. The proapoptotic effect of U0126 in the most sensitive cell line appeared to be related to CD34 positivity. Cells from leukemic patients showed considerable sensitivity in two of four cases with a similar association with CD34 expression being evident. Interestingly, control cells did not show a significant effect when exposed to the inhibitor. These results suggest that U0126 may offer a potential alternative to standard chemotherapy with a particular role in the most primitive types of leukemia, these being often the most resistant to standard chemotherapy.
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PMID:An investigation of the effects of the MEK inhibitor U0126 on apoptosis in acute leukemia. 1467 15

The aim was to study the roles of extracellular regulated protein kinases (ERK) and telomerase activity in drug resistance of human leukemia and ovarian carcinoma cells. Flow cytometry was used to analyze apoptosis rate. Telomere repeat amplification protocol (TRAP) and bioluminescence analysis method were used for detection of telomerase activity. The phosphorylated ERK(1/2) protein expression was observed by Western blot method. The results showed that the specific inhibitor PD98059 of ERK kinase 1 (MEK(1)) enhanced the sensitivity of HL-60/E6 leukemia cell lines to harringtonine (HRT) or COC1/DDP ovarian carcinoma cell lines to cis-dichlorodiamine platinum (DDP). Both PD98059 and chemotherapy drugs HRT and DDP reduced the phosphorylated ERK(1) and ERK(2) protein expression level, and down-regulated the telomerase activity. The sole action of each was inferior to the combination action of PD98059 and HRT or DDP. In conclusion, ERK and telomerase serve a function to some extent in drug resistance of leukemia and ovarian carcinoma cells. The inhibition of ERK signal transduction pathways led to reduction of phosphorylated ERK(1) and ERK(2) protein expression level, and successionally down-regulated the telomerase activity. The final result was to enhance the sensitivity of HL-60/E6 to HRT or COC1/DDP to DDP.
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PMID:[To inhibit ERK for enhancing chemotherapy sensitivity of drug-resistance cell lines of leukemia and ovarian carcinoma]. 1470 42

The roles of the JAK/STAT, Raf/MEK/ERK and PI3K/Akt signal transduction pathways and the BCR-ABL oncoprotein in leukemogenesis and their importance in the regulation of cell cycle progression and apoptosis are discussed in this review. These pathways have evolved regulatory proteins, which serve to limit their proliferative and antiapoptotic effects. Small molecular weight cell membrane-permeable drugs that target these pathways have been developed for leukemia therapy. One such example is imatinib mesylate, which targets the BCR-ABL kinase as well as a few structurally related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.
Leukemia 2004 Feb
PMID:JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. 1473 78

A number of extracellular stimuli, including soluble cytokines and insoluble matrix factors, are known to influence murine embryonic stem cell self-renewal and differentiation behavioral responses via intracellular signaling pathways, but their net effects in combination are difficult to understand. To gain insight concerning key intracellular signals governing these behavioral responses, we employ a multivariate systems analysis of proteomic data generated from combinatorial stimulation of mouse embryonic stem cells by fibronectin, laminin, leukemia-inhibitory factor, and fibroblast growth factor 4. Phosphorylation states of 31 intracellular signaling network components were obtained across 16 different stimulus conditions at three time points by quantitative Western blotting, and partial-least-squares modeling was used to determine which components were most strongly correlated with cell proliferation and differentiation rate constants obtained from flow cytometry measurements of Oct-4 expression levels. This data-driven, multivariate (16 conditions x 31 components x 3 time points = approximately 1,500 values) proteomic approach identified a set of signaling network components most critically associated (positively or negatively) with differentiation (Stat3, Raf1, MEK, and ERK), proliferation of undifferentiated cells (MEK and ERK), and proliferation of differentiated cells (PKB alpha, Stat3, Src, and PKC epsilon). These predictions were found to be consistent with previous in vivo literature, along with direct in vitro test here by a peptide inhibitor of PKC epsilon. Our results demonstrate how a computational systems biology approach can elucidate key sets of intracellular signaling protein activities that combine to govern cell phenotypic responses to extracellular cues.
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PMID:Multivariate proteomic analysis of murine embryonic stem cell self-renewal versus differentiation signaling. 1497 70

Arsenic is a well established human carcinogen and is associated with a variety of cancers including those of the skin. Paradoxically, arsenic has also been used, amid at low doses, in the treatment of leukemia for over a century. Here we demonstrate that low to moderate concentrations of arsenite (2-10 microm) that has little or no effect on normal melanocytes may induce apoptosis of human melanomas including highly metastatic ones despite their low surface Fas levels. The two prerequisites that dictate apoptotic response of melanomas upon arsenite treatment are low nuclear NF-kappaB activity and an endogenous expression of tumor necrosis factor alpha. Under these conditions, melanoma cells acquired sensitivity to tumor necrosis factor alpha-mediated killing. On the other hand, signaling pathways including those of phosphatidylinositol 3-kinase-AKT, MEK-ERK, and JNK play a protective role against arsenite-induced oxidative stress and apoptosis in melanoma cells. Suppression of these pathways dramatically accelerates arsenite-induced apoptosis. Taken together, these data could provide potential approaches to sensitize melanomas to the cytotoxic effects of arsenite through modulating the signaling pathways.
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PMID:Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor alpha-mediated pathway. 1502 28

Blockade of mitogen-activated protein kinase kinase (MEK1/2), part of the extracellular signal-regulated kinase (ERK) or p44/42 mitogen-activated protein kinase (MAPK) pathway, has been shown in some instances to cause apoptosis in leukemic blast cells. This investigation examined the effect of the potent MEK/ERK inhibitor U0126 on apoptosis in acute myeloblastic leukemia (AML) cell lines, and acute leukemic and non-leukemic patient samples. The pro-apoptotic effect of the inhibitor varied across the five cell lines tested (KG1a, HEL, TF-1, MO7e, and THP-1) from highly significant induction of apoptosis to no apparent response. The pro-apoptotic effect of U0126 in the most sensitive cell line, KG1a, appeared to be related to its CD34 positivity. Three of five leukemic bone marrow samples showed considerable sensitivity to the inhibitor and a similar association with CD34 expression was evident. Interestingly, control marrow cells from six non-leukemic patients did not show a significant effect when exposed to U0126. These results suggest that this agent may offer a potential alternative to standard chemotherapy with a particular role in the most primitive types of leukemia, these often being the most resistant to standard chemotherapy.
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PMID:An investigation of the MEK/ERK inhibitor U0126 in acute myeloid leukemia. 1503 99

The hierarchy of events accompanying induction of apoptosis by the proteasome inhibitor Bortezomib was investigated in Jurkat lymphoblastic and U937 myelomonocytic leukemia cells. Treatment of Jurkat or U937 cells with Bortezomib resulted in activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK (mitogen-activated protein kinase), inactivation of extracellular signal-regulating kinase 1/2 (ERK1/2), cytochrome c release, caspase-9, -3, and -8 activation, and apoptosis. Bortezomib-mediated cytochrome c release and caspase activation were blocked by the pharmacologic JNK inhibitor SP600125, but lethality was not diminished by the p38 MAPK inhibitor SB203580. Inducible expression of a constitutively active MEK1 construct blocked Bortezomib-mediated ERK1/2 inactivation, significantly attenuated Bortezomib lethality, and unexpectedly prevented JNK activation. Conversely, pharmacologic MEK/ERK1/2 inhibition promoted Bortezomib-mediated JNK activation and apoptosis. Lastly, the antioxidant N-acetyl-l-cysteine (LNAC) attenuated Bortezomib-mediated reactive oxygen species (ROS) generation, ERK inactivation, JNK activation, mitochondrial dysfunction, and apoptosis. In contrast, enforced MEK1 and ERK1/2 activation or JNK inhibition did not modify Bortezomib-induced ROS production. Together, these findings suggest that in human leukemia cells, Bortezomib-induced oxidative injury operates at a proximal point in the cell death cascade to antagonize cytoprotective ERK1/2 signaling, promote activation of the stress-related JNK pathway, and to trigger mitochondrial dysfunction, caspase activation, and apoptosis. They also suggest the presence of a feedback loop wherein Bortezomib-mediated ERK1/2 inactivation contributes to JNK activation, thereby amplifying the cell death process.
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PMID:The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. 1509 52

Activation of PKA by cAMP agonists, such as 8-Cl-cAMP activation, selectively causes rapid apoptosis in v-abl transformed fibroblasts by inhibiting the Raf-1 kinase. Here we investigated whether 8-Cl-cAMP is useful for the treatment of chronic myelogenous leukaemia (CML), which is hallmarked by the expression of the p210(bcr/abl) oncogene. Autologous bone marrow transplantation is a feasible alternative for patients with no suitable donor, but hampered by the risk of relapse due to the persistence of leukaemia cells in the transplant. To study the effects of 8-Cl-cAMP on primary leukaemic cells, bone marrow cells (BMCs) from eight CML patients (one at diagnosis, three in chronic and four in accelerated phase) were treated. Ex vivo treatment of BMCs obtained in chronic phase of CML with 100 microM 8-Cl-cAMP for 24-48 h led to the selective purging of Philadelphia Chromosome (Ph1 chromosome) without toxic side effects on BMCs from healthy donors as measured by colony-forming unit (CFU) assays. BMCs from patients in accelerated phase showed selective, but incomplete elimination of Ph1 chromosome positive colony forming cells. The mechanism of 8-Cl-cAMP was investigated in FDCP-mix cells transformed by p210(bcr/abl), a cell culture model for CML. The results showed that 8-Cl-cAMP reduced DNA synthesis and viability independent of Raf inhibition as Raf inhibitors had no effect. MEK inhibitors interfered with DNA synthesis, but not with viability. In summary, our results indicate that 8-Cl-cAMP could be useful to purge malignant cells from the bone marrow of patients with CML and certain other forms of leukaemias.
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PMID:Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for antileukaemic therapy. 1518 2

Use of all-trans-retinoic acid (ATRA) in combinatorial differentiation therapy of acute promyelocytic leukemia (APL) results in exceptional cure rates. However, potent cell differentiation effects of ATRA are so far largely restricted to this disease and long-term survival rates in non-APL acute myelogeneous leukemia (AML) remain unacceptably poor, requiring development of novel therapeutic strategies. We demonstrate here that myelomonocytic growth factors (granulocyte colony-stimulating factor [G-CSF] and/or granulocyte macrophage colony-stimulating factor [GM-CSF]) potentiate differentiation effects of ATRA in different AML cell lines and primary cells from patients with myeloid leukemia. The ligand-dependent activities of endogenous and transiently expressed retinoic acid receptor alpha (RARalpha) isoforms can be potentiated by G/GM-CSF in U-937 cells and correlate with increased expression of ATRA-inducible RARalpha2 isoform. Specific inhibitors of mitogen mitogen-activated protein kinase (MAPK) (MEK)-1/-2 or p38 extracellular signal-related kinase (ERK) kinase diminish the ATRA as well as ATRA and G/GM-CSF-induced activation of the RARalpha proteins and decreased the differentiation-induced decline in cell numbers. Our data demonstrate that acting, at least in part, via the MAP kinase pathways, myelomonocytic growth factors enhance ATRA-dependent activation of the RARalpha isoforms and maturation of myeloid leukemia cells. These results suggest that combinatorial use of these agents may be effective in differentiation therapy of AML.
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PMID:Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways. 1533 53


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