Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Busulfan (BU) is a unique alkylating agent that primarily targets slowly proliferating or nonproliferating cells in the body, leading to various normal tissue damage while killing leukemia cells. However, the mechanism(s) of action whereby BU injures normal cells has not been well defined and, therefore, was investigated in the present study by using the normal human diploid WI38 fibroblasts as a model system. We found that WI38 fibroblasts incubated with BU (from 7.5-120 microM) for 24 h underwent senescence but not apoptosis in a dose-independent manner, whereas cells incubated with 80 and 20 microM etoposide (Etop) were committed to apoptosis and senescence, respectively. The induction of WI38 cell senescence by Etop was associated with p53 activation and could be attenuated by down-regulation of p53 using alpha-pifithrin (alpha-PFT) or p53 small interference RNA (siRNA). In contrast, WI38 cell senescence induced by BU was associated with prolonged activation of extracellular signal-regulated kinase (Erk), p38 mitogen-activated protein kinase (p38), and c-Jun NH(2)-terminal kinase (JNK) and could be suppressed by the inhibition of Erk and/or p38 with PD98059 (2'-amino-3'-methoxyflavone) and/or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], respectively. However, inhibition of p53 with alpha-PFT or p53 siRNA or JNK with SP600125 (1,9-pyrazoloanthrone) failed to protect WI38 cells from BU-induced senescence. These findings suggest that BU is a distinctive chemotherapeutic agent that can selectively induce normal human fibroblast senescence through the Erk and p38 pathways.
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PMID:Busulfan selectively induces cellular senescence but not apoptosis in WI38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. 1688 77

Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As(2)O(3)) enhanced cell death of naturally As(2)O(3)-resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-l-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment-induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-l-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As(2)O(3) induces synergistic apoptosis in As(2)O(3)-resistant leukemia cells through the p38 MAPK-mediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As(2)O(3) treatment.
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PMID:Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide-resistant cancer cells. 1723 68

The leukemic cell line KG-1 was isolated from a patient with acute myeloid leukemia and is regarded a cellular model of human dendritic cell progenitors. The T helper type 1 cytokine interleukin (IL)-18 has been shown to induce the maturation of these cells towards a dendritic phenotype and, moreover, is able to mediate IFNgamma production in this model. Because T-box expressed in T cells (T-bet) is considered to be of paramount importance for dendritic cell function, the effects of IL-18 on this transcription factor have been investigated in the current study. Here, we show that activation of KG-1 cells by IL-18 induces T-bet mRNA and protein within 4 to 6 h of incubation. This hitherto unrecognized function of IL-18 was suppressed by the inhibition of p38 mitogen-activated protein kinase activity and nuclear factor-kappaB function. Blockage of translation by cycloheximide, usage of neutralizing antibodies, and the inability of IFNgamma to mediate significant p38 mitogen-activated protein kinase activation in KG-1 cells clearly revealed that activation of T-bet was not via autocrine IFNgamma. T-bet function was evaluated by short interfering RNA technology. Notably, specific suppression of T-bet induction impaired secretion of IFNgamma by KG-1 cells under the influence of IL-18. Therapeutic application of IL-18 has the potential to profoundly affect the biology of acute myeloid leukemia predendritic cells such as KG-1 cells. Under these conditions, activation of T-bet may play a key role in processes that have the potential to correct the T helper type 1 deficiency associated with leukemia-mediated immunosuppression.
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PMID:Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-kappaB in acute myeloid leukemia-derived predendritic KG-1 cells. 1730 68

The inactivation of synaptic serotonin (5-hydroxytryptamine, 5-HT) is largely established through the actions of the presynaptic, antidepressant-sensitive 5-HT transporter (SERT, SLC6A4). Recent studies have demonstrated post-translational regulation of SERT mediated by multiple Ser/Thr kinases, including protein kinases C and G (PKC and PKG) and p38 mitogen-activated protein kinase (MAPK), as well as the Ser/Thr phosphatase PP2A. Less well studied are specific surface receptors that target these signaling pathways to control SERT surface expression and/or catalytic rates. Using rat basophilic leukemia 2H3 cell line (RBL-2H3), we previously established that activation of A(3) adenosine receptors (A(3)AR) stimulates SERT activity via both PKG and p38 MAPK (Zhu et al., 2004a). Whether A(3)ARs regulate SERT in the central nervous system (CNS) is unknown. Here we report that the A(3)AR agonist N(6)-(3-iodobenzyl)-N-methyl-5'carbamoyladenosine (IB-MECA) rapidly (10 min) and selectively stimulates 5-HT transport in mouse midbrain, hippocampal, and cortical synaptosomes. IB-MECA-induced stimulation of 5-HT uptake is blocked by the selective A(3)AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(+/-)dihydropyridine-3,5-dicarboxylate (MRS1191) and is absent from synaptosomes prepared from A(3)AR knockout mice. Kinetic analyses demonstrate that IB-MECA induces an increase of 5-HT transport V(max) with no significant change in K(m). As in RBL-2H3 cells, IB-MECA stimulation of synaptosomal 5-HT uptake can be blocked by preincubation with PKG antagonists N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) and DT-2 (YGRKKRRQRRRPPLRK(5)H), as well as by the p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Chronoamperometry studies in the anesthetized rat hippocampus support a role for A(3)ARs in SERT regulation in vivo. Together, these results identify a novel, region-specific action of CNS A(3)ARs in the modulation of SERT-mediated 5-HT transport that may be relevant for the etiology and/or therapy of 5-HT-linked brain disorders.
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PMID:Rapid stimulation of presynaptic serotonin transport by A(3) adenosine receptors. 1746 Jan 50

Flavonoids are polyphenolic compounds that are ubiquitously in plants and display a vast array of biological activities. Here we have studied the effect of the phenylbenzo-gamma-pyrone-derivative quercetin 3-methyl ether tetracetate (QD), obtained by acetylation of the natural product quercetin 3-methyl ether, on cell viability of human leukemia HL-60 and U937 cell lines. The results show that QD was cytotoxic and induced G2-M phase cell cycle arrest on both cell lines and it was a potent apoptotic inducer on HL-60 cells. QD-induced apoptosis is (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk, (ii) associated with cytochrome c release and (iii) triggered in Bcl-2 over-expressing U937 cells. The treatment of HL-60 and U937 cells with QD also induces the activation of the mitogen-activated protein kinases (MAPKs) pathway, including c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases (ERK) 1/2. Inhibition of c-Jun N-terminal kinase by SP600125 and of p38 mitogen-activated protein kinase by SB203580 had no influence on QD-mediated apoptosis. In contrast, inhibition of ERK1/2 with the pharmacologic inhibitors U0126 or PD98059, together with QD, resulted in an important enhancement of apoptosis. Cells are sensitized to QD-mediated apoptosis after blocking ERK1/2, which suggests that inhibition of this pathway is a valuable strategy to increase the sensitivity of human leukemia HL-60 cells toward QD.
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PMID:Acetyl derivative of quercetin 3-methyl ether-induced cell death in human leukemia cells is amplified by the inhibition of ERK. 1754 1

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.
Leukemia 2007 Sep
PMID:Bortezomib inhibits human osteoclastogenesis. 1758 12

Conditionally replicating adenoviruses (CRAds) represent a promising new platform for anticancer therapy. However, CRAds have been evaluated little in hematopoietic malignancies because of the lack of expression of coxsackie adenovirus receptor (CAR) on their cell surface. In this study, we showed that CAR was expressed on two types of lymphoblastic leukemia cell lines and primary leukemia cells, and that ZD55, a CRAd, exerted a potent antileukemia effect in vitro and in vivo. Furthermore, ZD55 expressing melanoma differentiation-associated gene-7/interleukin-24 (ZD55-IL-24) elicited significant enhanced antileukemia activity comparing with ZD55, concomitant with upregulation of RNA-dependent protein kinase R (PKR), increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), and induction of endoplasmic reticulum (ER) stress. These data for the first time indicate that MDA-7/IL-24 exerts its antitumor effect on leukemia cells via multiple pathways, and suggest that oncolytic adenoviruses, ZD55 and ZD55-IL-24 could potentially be used against CAR-expressing hematological malignancies such as B-lymphoblastic leukemia/lymphoma and some myeloid leukemia.
Leukemia 2008 Feb
PMID:Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis. 1804 50

Production of interleukin (IL)-10, a major immunoregulatory cytokine, by phagocytes during clearance of apoptotic cells is critical to ensuring cellular homeostasis and suppression of autoimmunity. Little is known about the regulatory mechanisms in this fundamental process. We report that IL-10 production stimulated by apoptotic cells was regulated at the point of transcription in a manner dependent on p38 mitogen-activated protein kinase, partially on the scavenger receptor CD36, and required cell-cell contact but not phagocytosis. By using a reporter assay, we mapped the apoptotic-cell-response element (ACRE) in the human IL10 promoter and provide biochemical and physiological evidence that ACRE mediates the transcriptional activation of IL10 by pre-B cell leukemia transcription factor-1b and another Hox cofactor Pbx-regulating protein 1 in response to apoptotic cells. This study establishes a role of two developmentally critical factors (Pbx1 and Prep-1) in the regulation of homeostasis in the immune system.
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PMID:Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. 1809 41

In this study, we analysed 30 patients with B-cell chronic lymphocytic leukaemia (CLL), compared with 10 healthy donors, for the expression and function of the leukocyte-associated Ig-like receptor-1 (LAIR-1). LAIR-1 is an inhibitory receptor containing a cytoplasmic tyrosine-based inhibitory motif (ITIM) that binds to the SH2 domain of phosphatases, leading to dephosphorylation of different kinases. Constitutive activation of c-Jun aminoterminal kinase (JNK), p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, has been reported in CLL. We show that LAIR-1 is absent in high-risk (HR) CLL and differently expressed on intermediate- and low-risk CLL and the intensity of expression, which is always significantly lower than in healthy donors, correlates with disease stage and progression. Interestingly, both constitutive and sIgM-induced phosphorylation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal, as demonstrated by the use of specific ITIM-binding peptides; importantly, this inhibitory signal is missing when LAIR-1 is not expressed as occurs in HR CLL. Moreover, engagement of LAIR-1 blocks constitutive and sIgM-induced Akt phosphorylation, besides nuclear factor kappa-B nuclear translocation, and prevents CLL division. These results suggest that CLL lacking LAIR-1 may miss one of the molecular mechanisms controlling B-cell activation and proliferation.
Leukemia 2008 May
PMID:Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division. 1828 29

Interferon-alpha (IFN-alpha) has been used in the treatment of several cancers, including chronic myeloid leukemia. Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well known anti-malarial agent. We previously reported that artemisinin by itself caused a relatively low level of HL-60 cell differentiation. In this study, we investigated the effects of IFN-alpha in combination with artemisinin on cell growth and differentiation in HL-60 leukemia cells. Combination of IFN-alpha and artemisinin synergistically induced the levels of leukemia cell differentiation, although IFN-alpha by itself did not affect cell proliferation and differentiation. The increased cell differentiation by IFN-alpha and artemisinin was significantly suppressed by the inhibitors for protein kinase C (PKC), extracellular signal-regulated kinase (ERK) and jun N-terminal kinase (JNK), but not by the inhibitors for phosphatidylinositol 3-kinase (PI3-K) and p38 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with IFN-alpha increased levels of PKC alpha and phosphorylated ERK. Taken together, these results indicate the enhancement of artemisinin-induced HL-60 cell differentiation by IFN-alpha through the activation of a PKC alpha/ERK signaling pathway, and suggest a possible use of IFN-alpha and artemisinin in the treatment of leukemic diseases.
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PMID:Interferon-alpha enhances artemisinin-induced differentiation of HL-60 leukemia cells via a PKC alpha/ERK pathway. 1845 55


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