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)

The effect of ascorbate in reducing Adriamycin toxicity has been examined in mice and guinea pigs. Ascorbate had no effect on the antitumor activity of Adriamycin in mice inoculated with leukemia L1210, but it significantly prolonged the life of mice and guinea pigs treated with Adriamycin. Adriamycin elevated lipid peroxide levels in serum and liver, and ascorbate prevented the elevation. The significant prevention of Adriamycin-induced cardiomyopathy by ascorbate was proved by means of electron microscopy. The earliest alterations of dilation of the sarcoplasmic reticulum and transverse tubular system and the appearance of a large number of cytoplasmic fat droplets, which were seen in cardiac tissue from guinea pigs receiving Adriamycin, were apparently reduced in animals that were treated with ascorbate.
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PMID:Reduction of adriamycin toxicity by ascorbate in mice and guinea pigs. 705 58

Ascorbate, an essential nutrient in humans, primates, and guinea pig, is involved in many cellular functions. Ascorbate also modulates cell growth and differentiation. Ascorbate can reduce or stimulate the growth of tumor cells, depending on the cell type. The inhibitory effect is not specific for the biological active isomer L-ascorbate, and isoascorbate and D-ascorbate are more effective in reducing cell growth than L-ascorbate. These results indicate that ascorbate has a cytotoxic effect by killing cells directly, rather a cytostatic one. However, only L-ascorbate is able to stimulate cell growth, but the mechanism of this stimulation is still unknown. L-Ascorbate stimulates the in vitro differentiation of several mesenchyme-derived cell types by altering the expression of multiple genes as the cell progresses through specific differentiation programs. Stimulation of collagen matrix at gene transcription, mRNA stabilization, hydroxylation, and secretion is a key role for L-ascorbate. L-Ascorbate also prevents cell transformation by stabilization of the differentiated state and cooperates with other agents to induce differentiation in a leukemia cell line.
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PMID:Ascorbate on cell growth and differentiation. 784 14

Ascorbate is an important cofactor in many cellular metabolic reactions and is intimately linked to iron homeostasis. Continuously cultured cells are ascorbate deficient due to the lability of the vitamin in solution and to the fact that daily supplementation of media with ascorbate is unusual. We found that ascorbate repletion alone did not alter ferritin synthesis. However, ascorbate-replete human hepatoma cells, Hep3B and HepG2, as well as K562 human leukemia cells achieved a substantially higher cellular ferritin content in response to a challenge with iron than did their ascorbate-deficient counterparts grown under standard culture conditions. Most of the elevation in ferritin content was due to an increase in de novo ferritin synthesis of greater than 50-fold, as shown by in vivo labeling with [35S]methionine and immunoprecipitation. RNA-blot analysis showed only minor changes in steady state levels of ferritin mRNA, suggesting that ascorbate enhances iron-induced ferritin synthesis primarily by post-transcriptional events. Transient gene expression experiments using chloramphenicol acetyltransferase reporter gene constructs showed that the ascorbate effect on ferritin translation is not mediated through the stem-loop near the translational start site that transduces ferritin synthesis in response to cytokines. The data suggest that ascorbate possibly modifies the action of the iron-responsive element on ferritin translation, although more precise structure-function studies are needed to clarify this issue. These data demonstrate a novel role of ascorbate as a signaling molecule in post-transcriptional gene regulation. The mechanism by which ascorbate modulates cellular iron metabolism is complex and requires additional detailed investigation.
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PMID:Ascorbic acid enhances iron-induced ferritin translation in human leukemia and hepatoma cells. 785 59

Etoposide (VP-16) is extensively used to treat cancer, yet its efficacy is calamitously associated with an increased risk of secondary acute myelogenous leukemia. The mechanisms for the extremely high susceptibility of myeloid stem cells to the leukemogenic effects of etoposide have not been elucidated. We propose a mechanism to account for the etoposide-induced secondary acute myelogenous leukemia and nutritional strategies to prevent this complication of etoposide therapy. We hypothesize that etoposide phenoxyl radicals (etoposide-O(.)) formed from etoposide by myeloperoxidase are responsible for its genotoxic effects in bone marrow progenitor cells, which contain constitutively high myeloperoxidase activity. Here, we used purified human myeloperoxidase, as well as human leukemia HL60 cells with high myeloperoxidase activity and provide evidence of the following. 1) Etoposide undergoes one-electron oxidation to etoposide-O(.) catalyzed by both purified myeloperoxidase and myeloperoxidase activity in HL60 cells; formation of etoposide-O(.)radicals is completely blocked by myeloperoxidase inhibitors, cyanide and azide. 2) Intracellular reductants, GSH and protein sulfhydryls (but not phospholipids), are involved in myeloperoxidase-catalyzed etoposide redox-cycling that oxidizes endogenous thiols; pretreatment of HL60 cells with a maleimide thiol reagent, ThioGlo1, prevents redox-cycling of etoposide-O(.) radicals and permits their direct electron paramagnetic resonance detection in cell homogenates. VP-16 redox-cycling by purified myeloperoxidase (in the presence of GSH) or by myeloperoxidase activity in HL60 cells is accompanied by generation of thiyl radicals, GS(.), determined by HPLC assay of 5, 5-dimethyl-1-pyrroline glytathionyl N-oxide glytathionyl nitrone adducts. 3) Ascorbate directly reduces etoposide-O(.), thus competitively inhibiting etoposide-O(.)-induced thiol oxidation. Ascorbate also diminishes etoposide-induced topo II-DNA complex formation in myeloperoxidase-rich HL60 cells (but not in HL60 cells with myeloperoxidase activity depleted by pretreatment with succinyl acetone). 4) A vitamin E homolog, 2,2,5,7, 8-pentamethyl-6-hydroxychromane, a hindered phenolic compound whose phenoxyl radicals do not oxidize endogenous thiols, effectively competes with etoposide as a substrate for myeloperoxidase, thus preventing etoposide-O(.)-induced redox-cycling. We conclude that nutritional antioxidant strategies can be targeted at minimizing etoposide conversion to etoposide-O(.), thus minimizing the genotoxic effects of the radicals in bone marrow myelogenous progenitor cells, i.e., chemoprevention of etoposide-induced acute myelogenous leukemia.
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PMID:Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. 1046 37

Using E.coli bacteria (AB 1157) and leukemia cells (HL 60) as a model for in vitro studies it was established that the efficiency of mitomycin C (MMC) can be influenced in the presence of antioxidant vitamins. This synergistic effect of the vitamins C, E-acetate and beta-carotene on MMC activity is rather strong for E.coli bacteria under irradiation (15 and 50 Gy) in the presence of air. Vitamin C contributes more efficiently to the MMC-activity in leukemia cells than the other two vitamins. The effect is explained by a cascade electron transfer process from the vitamins to MMC, where vitamin C is acting as a major electron source. These results might be of importance in cancer therapy.
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PMID:Enhancement of mitomycin C efficiency by vitamin C, E-acetate and beta-carotene under irradiation. A study in vitro. 1069 55

It has been reported that several cis-unsaturated fatty acids (c-UFAs) could increase doxorubicin (DOX) accumulation in cancer cells and hence elevate its cytotoxicity. However, some researchers showed that c-UFA pretreatment did not affect its cytotoxicity in special cell lines. It is possible that the different results occurred due to different cellular characteristics. We hypothesized that c-UFA treatment might modulate the activities of some antioxidant enzymes to affect the resistance of cells to DOX. In the present study, we examined how c-UFA pretreatment affected DOX cytotoxicity on mouse leukemia cell line, P388, and its resistant subline, P388/DOX, which we found to have significantly higher glutathione peroxidase (GPx) activity as well as P-glycoprotein (p-gp) overexpression. We chose two c-UFAs, gamma-linolenic acid (GLA) (18:3n-6) and docosahexaenoic acid (DHA) (22:6n-3). Cytotoxicity was measured by MTT (3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and trypan blue exclusion assays. DOX accumulation and p-gp expression were measured by flow cytometry. The activities of catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and GPx were determined for both cell lines with and without treatment with GLA or DHA. Significant DOX accumulation occurred in both cell lines with GLA or DHA pretreatment, but without any change in p-gp expression in either cell line. Sensitivity to DOX cytotoxicity was improved by GLA or DHA pretreatment in P388/DOX in which only SOD activity was significantly increased, but not in the parental cell line P388 in which both SOD and CAT were significantly increased by the pretreatment. However, combined pretreatment of GLA or DHA with antioxidants, pyrrolidinedithiocarbamate (PDTC) or Vitamin C, could sensitize not only P388/DOX but also P388 cells to DOX. We conclude that the effects of c-UFA pretreatment on the sensitivity of cancer cells to DOX not only depend on the change in drug accumulation but also the change in the levels of antioxidant enzyme activities, and suggest that combined administration of c-UFAs, antioxidants, and DOX may be more effective in treating leukemia.
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PMID:Effects of cis-unsaturated fatty acids on doxorubicin sensitivity in P388/DOX resistant and P388 parental cell lines. 1095 54

Arsenic trioxide (As2O3) induces remission in a high proportion of patients with acute promyelocytic leukaemia (APL) via induction of apoptosis. Preliminary reports suggest that the apoptotic effect of As2O3 is not specific for APL but can also be observed in non-APL acute myeloid leukaemia (AML) cells, although these are less sensitive than APL cells. Ascorbic acid has recently been demonstrated to enhance the apoptotic effect of As2O3. We have therefore evaluated combined As2O3/ascorbic acid treatment in various clinical samples of AML. Our results indicate a significant synergistic effect of As2O3 and ascorbic acid, suggesting a possible future role of As2O3/ascorbic acid combination therapy in patients with AML.
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PMID:Arsenic trioxide and ascorbic acid: synergy with potential implications for the treatment of acute myeloid leukaemia? 1126 84

Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow leukaemic cells of a child with newly diagnosed ALL, after treatment with a single dose of VCR. We hypothesized that VCR induced apoptosis in ALL cells proceeds by a mitochondrial controlled pathway. We further studied the route of VCR induced apoptosis in Jurkat acute lymphoblastic leukaemia cells. First we showed that VCR induces activation of caspase-9 and -3 in Jurkat cells. With the caspase-9 inhibitor Z-LEHD-FMK we proved that caspase-9 was activated prior to caspase-3. Loss of mitochondrial transmembrane potential was independent of caspase-9 activation. To confirm the mitochondrial role in VCR induced apoptosis, the effect of blocking the mitochondrial route upstream of caspase-9 activation was investigated at two different levels: reactive oxygen species (ROS) scavenging and Bcl-2 overexpression. Generation of ROS was detected early in Jurkat cells during VCR exposure. Ascorbic acid, a ROS scavenger, inhibited ROS generation as well as caspase-9 and -3 activation and cell death induced by VCR. Furthermore, in Bcl-2 overexpressing Jurkat cells mitochondrial membrane potential changes, caspase-9 and -3 activation and cell death upon VCR exposure were decreased, in comparison to parental Jurkat cells. However, generation of ROS was not decreased in Jurkat cells with Bcl-2 overexpression. We concluded that ROS play a regulatory role in the initial phase of a mitochondrial controlled pathway of VCR induced apoptosis in Jurkat cells.
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PMID:Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: a mitochondrial controlled pathway regulated by reactive oxygen species? 1242 86

Acetaminophen, a common analgesic and antipyretic drug, is frequently administered to individuals undergoing anthracycline chemotherapy. Here, the effect of acetaminophen on the metabolism of daunorubicin and doxorubicin by isolated enzymes lactoperoxidase and myeloperoxidase, and by myeloperoxidase-containing human leukemia HL-60 cells was investigated using spectrophotometric and EPR techniques. We report that at pharmacological concentrations acetaminophen strongly stimulates oxidation of the anthracyclines by lactoperoxidase and myeloperoxidase systems, which results in irreversibly altered (colorless) products. The initial rate and efficacy of daunorubicin oxidation depends on pH. While at pH approximately 7 the oxidation is rapid and extensive, almost no oxidation occurs at pH approximately 5. In the absence of daunorubicin, oxidation of acetaminophen by lactoperoxidase/hydrogen peroxide is only weakly dependent on pH, however, at pH 7.4 it strongly depends on [daunorubicin]. Ascorbate and reduced glutathione strongly inhibited oxidation of anthracyclines by lactoperoxidase and HL-60 systems. Using EPR, a daunorubicin-derived radical was detected in a daunorubicin/acetaminophen/peroxidase/hydrogen peroxide system as a narrow single line (0.175 mT) with g = 2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g = 2.0043, line width approximately 0.5 mT). Similar results were obtained with doxorubicin. We suggest that the stimulation by acetaminophen is primarily due to its preferential oxidation by peroxidases to the corresponding phenoxyl radical, which subsequently reacts with daunorubicin (doxorubicin). Because biological properties of oxidatively transformed anthracyclines will certainly be different from those of their parent compounds, the possible acetaminophen-enhanced degradation of the anthracyclines in vivo is likely to interfere with anticancer and/or cardiotoxic activities of these agents.
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PMID:Acetaminophen stimulates the peroxidative metabolism of anthracyclines. 1517 84

AP9-cd, a standardized lignan composition from Cedrus deodara consisting of (-)-wikstromal, (-)-matairesinol, and dibenzyl butyrolactol, showed cytotoxicity in several human cancer cell lines reported earlier. An attempt was made in this study to investigate the mechanism of cell death in human leukemia Molt-4 and HL-60 cells. It inhibited Molt-4 cell proliferation with 48-h IC(50) of approximately 15 microg/ml, increased sub-G0 cell fraction with no mitotic block, produced apoptotic bodies and induced DNA ladder formation. Flow cytometric analysis of annexinV-FITC/PI-stained cells showed time-related increase in apoptosis and post-apoptotic necrosis. All these biological end-points indicated cell death by apoptosis. Further, initial events involved massive nitric oxide (NO) formation within 4 h with subsequent late appearance of peroxides in cells; measured by flow cytometry using specific fluorescent probes. Persistently high levels of NO and peroxide appeared to decrease mitochondrial membrane potential (Psi(mt)) which was recovered by cyclosporin A in Molt-4 cells. AP9-cd caused 2-fold activation of caspase-3 in Molt-4 and 5-fold activation in HL-60 cells. Also caspases-8 and -9 were activated in HL-60 cells. Ascorbate suppressed the enhanced caspases activities indicating a pro-oxidant effect of AP9-cd. Further, caspase-3 activation correlated with NO generation that was partially impaired by nitric oxide synthase (NOS) inhibitors and ascorbate suggesting a role of pro-oxidant species in caspase-3 activation. AP9-cd produced no cytotoxicity in primary rat hepatocyte culture at the concentrations used. The studies indicated that AP9-cd mediated early NO formation leads to caspases activation, peroxide generation, and mitochondrial depolarization which may be responsible for mitochondrial-dependent and -independent apoptotic pathways involved in the killing of leukemia cells by AP9-cd.
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PMID:A novel lignan composition from Cedrus deodara induces apoptosis and early nitric oxide generation in human leukemia Molt-4 and HL-60 cells. 1628 76


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