UMLS:C0023418 - FACTA Search

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

Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of reactive oxygen species (ROS) production on DNA damage and potentiation of fludarabine lethality by the histone deacetylase inhibitor (HDACI) LAQ-824 was investigated in human leukemia cells. Preexposure (24 h) of U937, HL-60, Jurkat, or K562 cells to LAQ-824 (40 nmol/L) followed by fludarabine (0.4 micromol/L) dramatically potentiated apoptosis (>or=75%). LAQ-824 triggered an early ROS peak (30 min-3 h), which declined by 6 h, following LAQ-824-induced manganese superoxide dismutase 2 (Mn-SOD2) upregulation. LAQ-824/fludarabine lethality was significantly diminished by either ROS scavengers N-acetylcysteine or manganese (III) tetrakis (4-benzoic acid) porphyrin or ectopic Mn-SOD2 expression and conversely increased by Mn-SOD2 antisense knockdown. During this interval, LAQ-824 induced early (4-8 h) increases in gamma-H2AX, which persisted (48 h) secondary to LAQ-824-mediated inhibition of DNA repair (e.g., down-regulation of Ku86 and Rad50, increased Ku70 acetylation, diminished Ku70 and Ku86 DNA-binding activity, and down-regulated DNA repair genes BRCA1, CHEK1, and RAD51). Addition of fludarabine further potentiated DNA damage, which was incompatible with cell survival, and triggered multiple proapoptotic signals including activation of nuclear caspase-2 and release of histone H1.2 into the cytoplasm. The latter event induced activation of Bak and culminated in pronounced mitochondrial injury and apoptosis. These findings provide a mechanistic basis for understanding the role of early HDACI-induced ROS generation and modulation of DNA repair processes in potentiation of nucleoside analogue-mediated DNA damage and lethality in leukemia. Moreover, they show for the first time the link between HDACI-mediated ROS generation and the recently reported DNA damage observed in cells exposed to these agents.
...
PMID:Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. 1885 32

Organosulfur compounds have been established to possess anticancer effects. To provide a better understanding of the biological function of dimethyl sulfides, dimethyl monosulfide (Me(2)S), dimethyl disulfide (Me(2)S(2)), dimethyl trisulfide (Me(2)S(3)) and dimethyl tetrasulfide (Me(2)S(4)) were used as experimental materials to investigate their effects on apoptosis induction in human leukemia Jurkat cells and HL-60 cells. Treatment with 20 muM dimethyl sulfides for 24 h decreased the viability of both cells. The cell viability-reducing effect of these sulfides was in the following order: Me(2)S(4) asymptotically equal to Me(2)S(3) > Me(2)S(2) asymptotically equal to Me(2)S for Jurkat cells and Me(2)S(4) > Me(2)S(3) > Me(2)S(2) asymptotically equal to Me(2)S for HL-60 cells. Me(2)S(3) and Me(2)S(4) significantly induced DNA fragmentation and caspase-3 activation. The addition of GSH or NAC completely suppressed the sulfide-induced apoptosis. Our results indicate that dimethyl sulfides with a larger number of sulfur atoms more strongly induced apoptosis in both human leukemia cells via ROS production and caspase-3 activation.
...
PMID:Effect of dimethyl sulfides on the induction of apoptosis in human leukemia Jurkat cells and HL-60 cells. 1899 6

In order to overcome chemotherapy resistance, many laboratories are searching for agents that increase the sensitivity of cancer cells to anticancer drugs. Arsenic trioxide (As(2)O(3)) is widely used in treating human acute polymyelocytic leukemia (APL). However, solid tumors and other leukemia cells such as U937 promonocytic leukemia cells are insensitive to As(2)O(3). Esculetin, a coumarin derivative, has previously induced cell cycle arrest and apoptosis of HL-60 cells as well as enhanced taxol-induced apoptosis in HepG2 cells, thereby displaying anticancer potential. In this study, esculetin inhibited proliferation and mitogen activated protein kinases (MAPKs) activation in human leukemia U937 cells. Since inhibitors of MAPKs have modulated the GSH-redox state and enhanced the sensitivity of leukemia cells to As(2)O(3)-provoked apoptosis, we monitored the effect of combining esculetin and As(2)O(3) (2.5 microM) on the GSH level. Our study showed that esculetin, PD98059 (MEK/ERK inhibitor), and SP600125 (JNK inhibitor) similarly enhanced the As(2)O(3)-induced GSH depletion. We found that the As(2)O(3) (2.5 microM) treatment slightly induced apoptosis and the pretreatment of esculetin enhanced the As(2)O(3)-provoked apoptosis significantly. In addition, esculetin enhanced the effect of As(2)O(3) on caspase activation in U937 cells. We compared the combined esculetin and As(2)O(3) treatment to the As(2)O(3) treated alone. The combined esculetin and As(2)O(3) treatment increased Bid cleavage, Bax conformation change and cytochrome C release. The study also indicated that esculetin enhanced the As(2)O(3)-induced lysosomal leakage and apoptosis. Furthermore, pretreatment with N-acetylcysteine (NAC) reduced these enhanced effects. Based on these studies, esculetin enhances the As(2)O(3)-provoked apoptosis by modulating the MEK/ERK and JNK pathways and reducing intracellular GSH levels. GSH depletion led to higher oxidative stress which activated lysosomal-mitochondrial pathway of apoptosis.
...
PMID:Enhancement of esculetin on arsenic trioxide-provoked apoptosis in human leukemia U937 cells. 1942 45

The proliferation and/or survival of a variety of cells is dependent on cellular hydrogen peroxide (H(2)O(2)) production. We tested whether this was true of leukemic cells, using cell lines from leukemic patients (CEM, 697, Mn-60, and Tanoue). We found that addition of catalase inhibited proliferation of all cell lines and induced death in two. However, this turned out to be due to arginase contamination of the catalase. Pure arginase inhibited cell proliferation and survival, which was reversible by adding L-arginine, demonstrating the L-arginine dependency of these cells. The glutathione peroxidase mimetic ebselen killed the cells by a novel, rapid form of death, preceded by cell blebbing and prevented by N-acetylcysteine, suggesting toxicity is not due to ebselen's antioxidant activity. Addition of N-acetylcysteine to remove endogenous H(2)O(2) stimulated survival and proliferation, suggesting that basal levels of H(2)O(2) promoted cell death. Consistent with this, leukemic cell death was induced by adding as little as 5 microM H(2)O(2). Ascorbic acid, even at 100 microM, induced death through H(2)O(2) production. Thus H(2)O(2) does not promote proliferation and survival, rather the opposite, and previous literature may have misinterpreted the effects of antioxidants. Arginase, H(2)O(2), ascorbic acid, and ebselen might be useful in the treatment of leukemia.
...
PMID:Dependence of leukemic cell proliferation and survival on H2O2 and L-arginine. 1943 12

We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DR5, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling pathways. The present study further demonstrates that reactive oxygen species (ROS) were generated in abundance in Jurkat leukemia cells upon AD5-10 stimulation and that ROS accumulation subsequently evoked sustained activation of c-Jun N-terminal kinase (JNK), loss of mitochondrial membrane potential, and release of endonuclease G (Endo G) from mitochondria into the cytosol. The reducing agent, N-acetylcysteine (NAC), effectively inhibited the sustained activation of JNK, release of Endo G, and cell death in Jurkat cells treated by AD5-10. Moreover, a dominant-negative form of JNK (but not of p38) enhanced NF-kappaB activation, suppressed caspase-8 recruitment in death-inducing signaling complexes (DISCs), and reduced adverse effects on mitochondria, thereby inhibiting AD5-10-induced cell death in Jurkat leukemia cells. These data provide novel information on the DR5-mediated cell death-signaling pathway and may shed new light on effective strategies for leukemia and solid tumor therapies.
...
PMID:An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells. 1946 86

N,N-dimethyl phytosphingosine (DMPS) blocks the conversion of sphingosine to sphingosine-1-phosphate (S1P) by the enzyme sphingosine kinase (SK). In this study, we elucidated the apoptotic mechanisms of DMPS action on a human leukemia cell line using functional pharmacologic and genetic approaches. First, we demonstrated that DMPS-induced apoptosis is evidenced by nuclear morphological change, distinct internucleosomal DNA fragmentation, and an increased sub-G1 cell population. DMPS treatment led to the activation of caspase-9 and caspase-3, accompanied by the cleavage of poly(ADP-ribose) polymerase (PARP) and led to cytochrome c release, depolarization of the mitochondrial membrane potential, and downregulation of the anti-apoptotic members of the bcl-2 family. Ectopic expression of bcl-2 and bcl-xL conferred resistance of HL-60 cells to DMPS-induced cell death, suggesting that DMPS-induced apoptosis occurs predominantly through the activation of the intrinsic mitochondrial pathway. We also observed that DMPS activated the caspase-8-Bid-Bax pathway and that the inhibition of caspase-8 by z-IETD-fmk or small interfering RNA suppressed the cleavage of Bid, cytochrome c release, caspase-3 activation, and apoptotic cell death. In addition, cells subjected to DMPS exhibited significantly increased reactive oxygen species (ROS) generation, and ROS scavengers, such as quercetin and Tiron, but not N-acetylcysteine (NAC), inhibited DMPS-induced activations of caspase-8, -3 and subsequent apoptotic cell death, indicating the role of ROS in caspase-8-mediated apoptosis. Taken together, these results indicate that caspase-8 acts upstream of caspase-3, and that the caspase-8-mediated mitochondrial pathway is important in DMPS-induced apoptosis. Our results also suggest that ROS are critical regulators of caspase-8-mediated apoptosis in DMPS-treated leukemia cells.
...
PMID:N,N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells. 1948 59

A number of neurotoxic agents could potentially exert their action by degrading or modifying cytoskeleton components like neurofilaments (NF). Cytosine arabinoside (AraC) is an anticancer drug commonly used in leukemia treatment. Its side effects include neuronal cell death in the cerebellum and severe motor coordination deficits. We have previously shown that AraC administration (400mg/kg bw) in adult rats reduced NF immunostaining in cerebellar neurons. To further delineate the susceptibility of individual NF isoforms (NF-H, NF-M, NF-L) to AraC, in the present study we used Western blot analysis to quantify their level. A significant and selective reduction of NF-H isoform was observed in the cerebellum of AraC-treated animals, compared to the controls. Administration of the antioxidant N-acetylcysteine (NAC) for a period of 14 days (prior to and during AraC treatment), which was previously shown to ameliorate the AraC-induced motor deficits in these animals, largely prevented the reduction in NF-H isoform. Given the significant role of NF proteins and particularly NF-H in maintaining structural integrity and synaptic transport, the observed loss of this isoform may be a key-target of AraC action in cerebellar neurons. Moreover, this study provides further data on the neuroprophylactic role of NAC in vivo against chemotherapy-induced toxicity.
...
PMID:Neurofilament isoform alterations in the rat cerebellum following cytosine arabinoside administration. 1952 8

Methoctramine and its analogues are polymethylene tetramines that selectively bind to a variety of receptor sites. Although these compounds are widely used as pharmacological tools for receptor characterization, the toxicological properties of these polyamine-based structures are largely unknown. We have evaluated the cytotoxic effects of methoctramine and related symmetrical analogues differing in polymethylene chain length between the inner nitrogens against a panel of cell lines. Methoctramine caused cell death only at high micromolar concentrations, whereas its pharmacological action is exerted at nanomolar level. Increasing the spacing between the inner nitrogen atoms resulted in a significative increase in cytotoxicity. In particular, an elevated cytotoxicity is associated to a methylene chain length of 12 units dividing the inner amine functions (compound 5). H9c2 cardiomyoblasts were the most sensitive cells, followed by SH-SY5Y neuroblastoma, whereas HL60 leukaemia cells were much more resistant. Methoctramine and related compounds down-regulated ornithine decarboxylase, the first enzyme of polyamine biosynthesis even at non-toxic concentration. Further, methoctramine and compound 5 caused a limited up-regulation of spermine/spermidine N-acetyltransferase, suggesting that interference in polyamine metabolism is not a primary mechanism of toxicity. Methoctramine and its analogues bound to DNA with a higher affinity than spermine, but the correlation with their toxic effect was poor. The highly toxic compound 5 killed the cells in the absence of caspase activation and caused an increase in p53 expression and ERK1/2 phosphorylation. Compound 5 was directly oxidized by cell homogenates producing hydrogen peroxide and its toxic effect was partially subdued by the inhibition of its uptake, by the NMDA ligand MK-801, and by the antioxidant N-acetylcysteine, suggesting that compound 5 can act at different cellular levels and lead to oxidative stress.
...
PMID:Cytotoxicity of methoctramine and methoctramine-related polyamines. 1957 91

Arachidonic acid (AA)-induced apoptotic death of human leukemia U937 cells was characteristic of increase in intracellular Ca(2+) concentration ([Ca(2+)]i), ROS generation, ERK inactivation, p38 MPAK activation, degradation of procaspase-8 and production of truncated Bid (tBid). Moreover, AA treatment upregulated Fas/FasL protein expression and transcription of Fas/FasL mRNA. Downregulation of FADD blocked AA-induced procaspase-8 degradation and rescued viability of AA-treated cells. BAPTA-AM (Ca(2+) chelator) pretreatment abolished AA-induced ROS generation, while N-acetylcysteine (NAC, ROS scavenger) was unable to alter AA-elicited [Ca(2+)]i increase. Pretreatment with BAPTA-AM or NAC abrogated p38 MAPK activation and restored ERK activation. Suppression of p38 MAPK or transfection of constitutively active MEK1 abolished AA-induced Fas and FasL upregulation. AA treatment repressed ERK-mediated c-Fos phosphorylation but evoked p38 MAPK-mediated ATF-2 phosphorylation. Knockdown of c-Fos and ATF-2 by siRNA reflected that c-Fos counteracted the effect of ATF-2 on Fas/FasL upregulation. Taken together, our data indicate that Fas/FasL upregulation in AA-treated U937 cells is elicited by Ca(2+)/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2, and suggest that autocrine Fas-mediated apoptotoic mechanism is involved in AA-induced cell death.
...
PMID:Arachidonic acid induces Fas and FasL upregulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2 pathway. 1972 Jan 22

The authors previously reported that costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, induced apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. In the present study, the authors investigated whether mitogen-activated protein kinases (MAPKs) are involved in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells. Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 min of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis. Furthermore, pretreatment with the antioxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. Pretreatment with SP600125 recovered the costunolide-suppressed Bcl-2 expression. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 d) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model.
...
PMID:Costunolide-induced apoptosis in human leukemia cells: involvement of c-jun N-terminal kinase activation. 1980 48

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>