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: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis-resistant K562 cells and apoptosis-proficient HL-60 acute myelomonocytic leukemia cells were selected to study the cell-type-specific characteristics of docetaxel. The kinetics of cytotoxicity of docetaxel showed a delayed response of K562 cells compared to HL-60 cells. After treatment with 10(-8)M docetaxel, DNA fragmentation and sub-G0/G1 cells were evident in HL-60 cells in less than 6 h, while K562 cells gradually arrested in G2/M phase of the cell cycle and appeared normal for 24 h before developing similar apoptotic changes. The delayed apoptotic changes in K562 cells were accompanied by delayed activation of caspase-3. Additionally, NADPH oxidase inhibition with diphenylene iodonium showed that reactive oxygen species (ROS) burst mediated critically in the caspase-3 activation and apoptosis in HL-60 cells but was only partially involved in those events of K562 cells. These results suggested that docetaxel exposure triggered the delayed apoptosis in K562 cells and the different ROS-dependent or independent signal pathways might account for this phenomenon. Docetaxel elicited ROS production from NADPH oxidase, which in turn triggered activation of caspase-3, leading to apoptosis in HL-60 cells. While in K562 cells, docetaxel induced apoptosis after G2/M accumulation through ROS-independent or partially dependent pathways.
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PMID:Comparison of burst of reactive oxygen species and activation of caspase-3 in apoptosis of K562 and HL-60 cells induced by docetaxel. 1533 Nov 78

The main anticancer action of doxorubicin (DOX) is believed to be due to topoisomerase II inhibition and free radical generation. Our previous study has demonstrated that TAS-103, a topoisomerase inhibitor, induces apoptosis through DNA cleavage and subsequent H(2)O(2) generation mediated by NAD(P)H oxidase activation [H. Mizutani et al. J. Biol. Chem. 277 (2002) 30684-30689]. Therefore, to clarify whether DOX functions as an anticancer drug through the same mechanism or not, we investigated the mechanism of apoptosis induced by DOX in the human leukemia cell line HL-60 and the H(2)O(2)-resistant sub-clone, HP100. DOX-induced DNA ladder formation could be detected in HL-60 cells after a 7 h incubation, whereas it could not be detected under the same condition in HP100 cells, suggesting the involvement of H(2)O(2)-mediated pathways in apoptosis. Flow cytometry revealed that H(2)O(2) formation preceded the increase in Delta Psi m and caspase-3 activation. Poly(ADP-ribose) polymerase (PARP) and NAD(P)H oxidase inhibitors prevented DOX-induced DNA ladder formation in HL-60 cells. Moreover, DOX significantly induced formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an indicator of oxidative DNA damage, in HL-60 cells at 1 h, but not in HP100 cells. DOX-induced apoptosis was mainly initiated by oxidative DNA damage in comparison with the ability of other topoisomerase inhibitors (TAS-103, amrubicin and amrubicinol) to cause DNA cleavage and apoptosis. These results suggest that the critical apoptotic trigger of DOX is considered to be oxidative DNA damage by the DOX-induced direct H(2)O(2) generation, although DOX-induced apoptosis may involve topoisomerase II inhibition. This oxidative DNA damage causes indirect H(2)O(2) generation through PARP and NAD(P)H oxidase activation, leading to the Delta Psi m increase and subsequent caspase-3 activation in DOX-induced apoptosis.
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PMID:Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. 1568 Mar 9

The expression status of mitochondrial uncoupling protein 2 (UCP2) was investigated in undifferentiated mouse myeloid leukemia (M1) and its differentiated macrophage-like cells (Mm1). Mm1 cells have a high ability of phagocytosis along with significantly high levels of reactive oxygen species (ROS) production, UCP2 protein and manganese superoxide dismutase (Mn-SOD), in contrast to undifferentiated leukemia cells (M1). Mm1 cells expressed 10-fold more UCP2 protein compared with undifferentiated M1 cells, although the UCP2 mRNA levels in both cell types were similar. The higher expression of UCP2 in the Mm1 cells suggests a regulatory role of UCP2 in the ROS production. Furthermore, the transfection of UCP2-GFP-expression vector in Mm1 cells dissipated the mitochondrial membrane potential and reduced ROS production, which was shown by their direct visualization using MitoTracker Red CM-H2Xros. The macrophage gp91phox protein, a membrane catalytic component of the NADPH oxidase complex, was at a similar level in both of UCP2-GFP expressed and non-expressed Mm1 cells. These results suggest that the UCP2 protein of the undifferentiated cell is regulated at a quite low level and the higher UCP2 protein of the differentiated macrophages involves with the regulation of ROS production.
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PMID:Characterization of the differential expression of uncoupling protein 2 and ROS production in differentiated mouse macrophage-cells (Mm1) and the progenitor cells (M1). 1570 97

Chronic disseminated candidiasis is a serious fungal infection in immunocompromised patients, particularly those undergoing therapy for acute leukemia. Coordination between innate and adaptive immune system is critical to resistance or susceptibility to Candida infection. In order to investigate possible genetic contribution to chronic disseminated candidiasis of key molecules in the innate immune pathway, we performed a case control study using the candidate gene approach. Forty subjects with chronic disseminated candidiasis and 50 controls without chronic disseminated candidiasis but an underlying diagnosis of leukemia were enrolled in the Helsinki University Central Hospital during the period 1980-1998. Candidate genes were selected for analysis based upon the following criteria: a common polymorphism (>5% frequency) and existence a priori of clinical and biological data suggesting a role for the variant in the pathogenesis of chronic disseminated candidiasis. Six genes were selected from critical microbicidal and innate immune pathways, including three low-affinity Fcgamma receptors (FCGR2A, FCGR3A and FCGR3B), chitotriosidase (CHIT1), p22-phox NADPH oxidase (CYBA), and mannose binding lectin (MBL2). There was no statistically significant association of susceptibility to chronic disseminated candidiasis with the polymorphisms in this study. Common variants in the six studied genes most likely do not contribute to the risk for chronic disseminated candidiasis in patients with acute leukemia.
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PMID:Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients. 1611 Jul 81

The hierarchy of events accompanying induction of apoptosis by the microtubule inhibitor docetaxel was investigated in HL-60 human leukemia cells. Treatment of HL-60 cells with docetaxel resulted in the production of reactive oxygen species (ROS), activation of caspase-3 (-like) protease, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation, bcl-2 phosphorylation and apoptosis. Docetaxel elicited ROS production from NADPH oxidase as demonstrated by specific oxidase inhibitor diphenylene iodonium (DPI). ROS mediated the caspase-3 activation and apoptosis in HL-60 cells. The caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) effectively inhibited JNK/SAPK activation, bcl-2 phosphorylation and partially attenuated the ROS production induced by docetaxel. Docetaxel-induced bcl-2 phosphorylation was completely blocked by expression of dominant negative JNK or the JNK/SAPK inhibitor SP600125. Overexpression of bcl-2 partially prevented docetaxel-mediated ROS production and subsequent caspase-3 activation, thereby inhibiting apoptotic cell death. It is thus conferred that such sequent events as ROS production, caspase activation, JNK/SAPK activation, bcl-2 phosphorylation and the further generation of ROS should be parts of an amplification loop to increase caspase activity, thereby facilitating the apoptotic cell death process.
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PMID:Amplification loop cascade for increasing caspase activity induced by docetaxel. 1614 76

Salicylate and jasmonates are two different types of plant hormone that play critical roles in plant defense responses against insect herbivores and microbial pathogens, through activating defense genes. These two natural products have been shown to have similar activities in animal cells: the compounds are able to induce cell cycle arrest or apoptosis in a variety of human cancer cells including those of colon, prostate, breast, and leukemia, suggesting the chemicals may potentially be a novel class of anti-cancer drugs. Since sodium salicylate can induce the heat shock response in animals, we examined the effects of jasmonates on the heat shock response in C6 glioma cells. Here, we show that brief exposure to methyl jasmonate (MeJA), but not to jasmonic acid, induces heat shock protein 72 (HSP72), but not HSP73 and HSP90, via heat shock factor I (HSF1) activation in C6 glioma cells without affecting cell viability. Intracellular H2O2 and O2-, and mitochondrial ROS were prominently increased in response to 5 mM MeJA in C6 cells. MeJA-induced HSP72 expression, HSF1 DNA binding, and human HSP70 promoter-driven CAT activity were prevented by N-acetyl-L-cysteine (a general antioxidant), catalase (a specific antioxidant for H2O2), and sodium formate (an inhibitor of OH.), but not by Rac1 dominant negative mutant Rac1N17 and diphenyleneiodonium (a NADPH oxidase inhibitor), indicating that MeJA induces HSP72 expression though HSF1 that is activated via Rac1-NADPH oxidase-independent ROS production pathway. These results suggest that the plant stress hormones share the ability to induce heat shock response in animal cells.
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PMID:Induction of heat shock protein 72 in C6 glioma cells by methyl jasmonate through ROS-dependent heat shock factor 1 activation. 1621 Dec 52

In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo. From a mechanistic standpoint, cannabidiol exposure resulted in activation of caspase-8, caspase-9, and caspase-3, cleavage of poly(ADP-ribose) polymerase, and a decrease in full-length Bid, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome c. It is noteworthy that cannabidiol exposure led to an increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases Nox4 and p22(phox). Furthermore, cannabidiol-induced apoptosis and reactive oxygen species (ROS) levels could be blocked by treatment with the ROS scavengers or the NAD(P)H oxidase inhibitors. Finally, cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22(phox) expression, may be a novel and highly selective treatment for leukemia.
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PMID:Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. 1675 84

Promyelocytic NB4 leukemia cells undergo differentiation to granulocytes following retinoic acid treatment. Here we report that tissue transglutaminase (TG2), a protein cross-linking enzyme, was induced, then partially translocated into the nucleus, and became strongly associated with the chromatin during the differentiation process. The transglutaminase-catalyzed cross-link content of both the cytosolic and the nuclear protein fractions increased while NB4 cells underwent cellular maturation. Inhibition of cross-linking activity of TG2 by monodansylcadaverin in these cells led to diminished nitroblue tetrazolium (NBT) positivity, production of less superoxide anion, and decreased expression of GP91PHOX, the membrane-associated subunit of NADPH oxidase. Neutrophils isolated from TG2(-/-) mice showed diminished NBT reduction capacity, reduced superoxide anion formation, and down-regulation of the gp91phox subunit of NADPH oxidase, compared with wild-type cells. It was also observed that TG2(-/-) mice exhibited increased neutrophil phagocytic activity, but had attenuated neutrophil chemotaxis and impaired neutrophil extravasation with higher neutrophil counts in their circulation during yeast extract-induced peritonitis. These results clearly suggest that TG2 may modulate the expression of genes related to neutrophil functions and is involved in several intracellular and extracellular functions of extravasating neutrophil.
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PMID:Tissue-transglutaminase contributes to neutrophil granulocyte differentiation and functions. 1676 14

The present study has demonstrated a differential cytotoxicity of stellettin A (1) between human leukemia HL-60 cells (IC50 0.4 microg/mL) and human prostate cancer LNCaP cells (IC50 120 microg/mL). Treatment of cells with 1 revealed the activation of NADPH oxidase, the dramatic generation of reactive oxygen species, and the dissipation of mitochondrial membrane potentials, with HL-60 cells being more sensitive than LNCaP cells by an order of magnitude. Immunoblotting analysis further demonstrated a stronger upregulation of the apoptosis marker proteins, FasL and caspase-3, in HL-60 cells, and pretreatment of cells with antisense oligonucleotide for caspase-3 abolished apoptosis. All available evidence suggests that 1 induces oxidative cell death through a FasL-caspase-3-apoptotic pathway.
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PMID:Stellettin A induces oxidative stress and apoptosis in HL-60 human leukemia and LNCaP prostate cancer cell lines. 1679 13

All methods used for quantitation of superoxide have limitations when it comes to differentiating between extracellular and intracellular sites of superoxide production. In the present study, we monitored dihydroethidium (DHE)-derived fluorescence at 570 nm, which indicates hydroxyethidium derived from reaction with superoxide produced by human leukemia cells (HL-60) and microvascular endothelial cells (HMEC-1). Phorbol-12-myristate 13-acetate (PMA; 100 ng/ml) caused an increase in fluorescence and lucigenin chemiluminescence in HL-60, which was abolished by superoxide dismutase (SOD; 600 U/ml) indicating that DHE detects extracellular superoxide. Furthermore, both HL-60 cells and HMEC-1 generated a fluorescence signal in the presence of DHE under resting conditions, which was unaffected by SOD, but abolished by polyethylene glycosylated-SOD (PEG-SOD) (100 U/ml) and MnTmPyP (25 microM), indicating that DHE also detects superoxide produced intracellularly. In HMEC-1, silencing of either Nox2 or Nox4 components of NADPH oxidase with small interference RNA (siRNA) resulted in a significant reduction in superoxide detected by both DHE fluorescence (Nox2 siRNA; 71 +/- 6% and Nox4 siRNA 83 +/- 7% of control) and lucigenin chemiluminescence (Nox2; 54 +/- 6% and Nox4 74 +/- 4% of control). In conclusion, DHE-derived fluorescence at 570 nm is a convenient method for detection of intracellular and extracellular superoxide produced by phagocytic and vascular NADPH oxidase.
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PMID:Analysis of dihydroethidium fluorescence for the detection of intracellular and extracellular superoxide produced by NADPH oxidase. 1751 43


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