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)

Butyric acid (BA) induces differentiation of human leukemia, including HL-60 cells. By using a fluorescent probe, we showed that reactive oxygen species (ROS) were generated in BA-treated cells. BA-induced differentiation was accompanied with an increased secretion of pro-matrix metalloproteinase (MMP)-9. Both phenomena were inhibited by antioxidants. Tissue inhibitors of MMP (TIMP)-1 and -2 secretion were increased by BA, but differently affected by antioxidants. By contrast, BA did not affect MMP-9 mRNA, and decreased TIMP-1 and TIMP-2 mRNA levels. In addition, migratory and invasive properties of HL-60 cells were enhanced by BA, but differently affected by antioxidants. Altogether, these results indicate that ROS are messengers of BA-induced differentiation and increased invasiveness.
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PMID:Butyric acid increases invasiveness of HL-60 leukemia cells: role of reactive oxygen species. 1199 38

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were demonstrated to have important implications in the progression and invasiveness of many malignant disorders. In contrast, the biological significance of these molecules in human leukaemias is not clear. We determined the levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the bone marrow of 37 patients with acute myelogenous leukaemia (AML) and 18 patients with acute lymphoblastic leukaemia (ALL) before chemotherapy. Nineteen bone marrow donors served as normal controls. After chemotherapy, sequential measurements were done during the course in 19 AML patients. The levels of TIMP-1 and TIMP-2 were significantly higher and MMP-9 levels were significantly lower in the AML and ALL patients than in the normal controls. MMP-2 levels were higher in ALL, but not AML patients, compared with controls. Moreover, the levels of marrow MMP-2 and MMP-9 did not parallel the numbers of leukaemic blasts in the peripheral blood. MMP-9 levels were significantly lower in the AML patients who achieved a complete remission (CR) than in those who did not (8.71 +/- 8.15 ng/ml vs 26.13 +/- 27.75 ng/ml, P < 0.05). The AML patients with lower MMP-9 levels (< or = 4.4 ng/ml) tended to have longer survival time than those with higher levels (> 12 months vs 4 months, P = 0.12). In addition, MMP-9 levels in the AML patients at CR rose to the same range as the controls, but dropped again at relapse, demonstrating a close relationship of marrow MMP-9 with disease status of AML. Therefore, we conclude that the level of marrow MMP-9 may be a useful surrogate marker for monitoring disease status in AML and propose it as a potential prognostic factor.
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PMID:Marrow matrix metalloproteinases (MMPs) and tissue inhibitors of MMP in acute leukaemia: potential role of MMP-9 as a surrogate marker to monitor leukaemic status in patients with acute myelogenous leukaemia. 1206 Jan 18

Aclarubicin (ACLA), which belongs to the anthracycline class of antineoplastic agents, has been demonstrated as a differentiating agent of human leukemia, including HL-60 cells. We report here on the incidence of ACLA-induced differentiation on matrix metalloproteinase (MMP) expression and cell invasiveness. The aim of this study was to investigate the involvement of reactive oxygen species (ROS) as mediators of ACLA-induced effects. By using a fluorescent probe, we showed that subtoxic (i.e. differentiating) concentration of ACLA generate reactive oxygen species in HL-60 cells. ACLA-differentiated cells exhibited an increased proMMP-9 secretion which has been observed by gelatin zymography and immunoassay. Antioxidants were able to inhibit ACLA-induced differentiation and proMMP-9 secretion. Furthermore, RT-PCR showed that ACLA increased MMP-9 and tissue inhibitor of MMP (TIMP-1) expression in a ROS-dependent manner. In addition, the migration and invasion capacities of HL-60 cells were enhanced by ACLA treatment, but only partially reversed by antioxidants. Altogether, these results evidenced ROS as messengers of ACLA-induced differentiation and MMP-9 expression.
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PMID:Involvement of reactive oxygen species in aclarubicin-induced differentiation and invasiveness of HL-60 leukemia cells. 1211 37

Eicosapentaenoic acid (EPA; 20:5n-3) may reduce the cell number in cultured leukemia/lymphoma cells owing to reduced cell proliferation, induction of cell death, or a combination of these processes. EPA has been shown to promote apoptosis in Ramos cells, and our present study was focused on a possible cell cycle arrest and the pathways by which the apoptotic process is induced. Apoptosis may proceed along the intrinsic (mitochondrial) or the extrinsic (death receptor) pathway, which are mediated via different caspases. Caspases are a class of homologous cysteine proteases recognized as pivotal mediators of apoptosis. We investigated whether EPA affects progression of the cell cycle or promotes apoptosis directly. By incorporation of [3H]thymidine and [3H]valine, we showed that DNA, as well as protein synthesis, was reduced after incubation of Ramos cells with EPA for 6 h. We monitored cell cycle distribution by 5-bromo-2'-deoxyuridine staining and observed no cell cycle arrest in the EPA-incubated cells. Incubation of cells with EPA caused PS-flipping, as demonstrated by annexin V-binding (flow cytometry), and cleavage of poly(ADP-ribose) polymerase measured by Western blot analysis. Furthermore, we observed increased activity of caspase-3 and -9, but not of caspase-8. Whereas inhibitors of caspase-3 and -9 reduced EPA-induced apoptosis, inhibition of caspase-8 did not. This suggests that EPA may promote apoptosis via the intrinsic pathway in Ramos cells. Thus, the reduction in cell number can be explained by a direct apoptotic effect of EPA rather than via cell cycle arrest.
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PMID:Eicosapentaenoic acid promotes apoptosis in Ramos cells via activation of caspase-3 and -9. 1237 51

The term "asbestos" has a commercial/industrial derivation limited to naturally occurring fibrous minerals of the serpentine or amphibole series. Chrysotile is the only type of asbestos in the serpentine series, whereas the amphibole series is represented by actinolite, amosite, anthophyllite, crocidolite, and tremolite. The essential characteristic of asbestos minerals is their fibrous nature. Large portions of the population ingest asbestos through consumption of food and water. Asbestos or asbestos-like fibers may gain access to water supplies as a result of mining (Lake Superior), from the presence of natural serpentine or amphibole deposits in watersheds (Seattle, WA, and San Francisco, CA) or, under certain conditions, through the use of asbestos-cement pipes for municipal water supplies. For the latter, erosion of the pipe with release of fibers is associated with the "aggressiveness" of the water, a term representing a mathematical expression of pH, alkalinity, and calcium content. The EPA estimated that 68.5% of water systems in the United States utilize water that is potentially capable of eroding asbestos-cement pipe. Carcinogenesis studies of amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted in male and female rats. Amosite asbestos was administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. One group of amosite asbestos-exposed rats (amosite preweaning gavage) also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. Litter size was the same, but the offspring from mothers exposed to amosite asbestos were smaller at weaning than those from nonexposed mothers and remained smaller throughout their life. The DMH was administered by gavage at a dose of 7.5 mg/kg for males and 15 mg/kg for females every 14 days, starting at 8 weeks of age, for a total of five doses. The administration of DMH did not affect body weight gain either in amosite-exposed or nonexposed animals. The amosite-exposed rats showed enhanced survival compared with that of the nonexposed rats. DMH exposure reduced survival by approximately 1 year, although the survival of the amosite plus DMH groups was slightly greater than that of the DMH group alone. Significant increases in the incidences of C-cell carcinomas of the thyroid gland (untreated control, 11/117; amosite, 50/246, P<0.05; amosite preweaning gavage, 14/100) and of leukemia (38/117; 106/249, P<0.05; 49/100, P<0.01) in male rats were observed in amosite-exposed groups. However, the biologic significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and because the positive effect was not observed in the amosite preweaning gavage group. The biologic significance of an increased incidence of leukemia is questionable because of a lack of statistical significance in the amosite group when evaluated by life table analysis and because no toxic lesions were observed in the target organs, i.e., gastrointestinal tract and mesothelium. DMH caused a high incidence (62%-74%) of intestinal neoplasia in amosite-exposed and nonexposed groups. Neither an enhanced carcinogenic nor a protective effect was demonstrated by exposure to amosite asbestos. Conclusions: Under the conditions of these feed studies, amosite asbestos was not overtly toxic, did not affect survival, and was not carcinogenic when ingested at a concentration of 1% in the diet by male or female F344/N rats. The cocarcinogenic studies using DMH were considered inadequate because of the high incidence of DMH-induced intestinal neoplasia in both the amosite asbestos-exposed and nonexposed groups. Levels of Evidence of Carcinogenicity: Amosite Asbestos: Male Rats: Negative. Female Rats: Negative. Amosite Asbestos + DMH: Male Rats: Inadequate. Female Rats: Inadequate. Note: Amosite Asbestos was previously tested in Syrmosite Asbestos was previously tested in Syrian Golden Hamsters administered in feed (See TR-249, reported 1983).
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PMID:NTP Toxicology and Carcinogenesis Studies of Amosite Asbestos (CAS No. 12172-73-5) in F344/N Rats (Feed Studies). 1274

The US Environmental Protection Agency recently released its new guidelines for carcinogen risk assessment together with supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. In particular, these guidelines encourage the use of mechanistic data in support of dose-response characterization at doses below those at which an increase in tumor frequency over background levels might be detected. In this context of the utility of mechanistic data for human cancer risk assessment, the International Life Sciences Institute (ILSI) has developed a human relevance framework (HRF) that can be used to assess the plausibility of a mode of action (MoA) described for animal models operating in humans. The MoA is described as a sequence of key events and processes that result in an adverse outcome. A key event is a measurable precursor step that is in itself a necessary element of the MoA or is a bioindicator for such an element. A number of cellular and molecular perturbations have been identified as key events whereby DNA-reactive chemicals can produce tumors. These include DNA adducts in target tissues, gene mutations and/or chromosomal alterations in target tissues and enhanced cell proliferation in target tissues. This type of data integration approach to quantitative cancer risk assessment can be applied to 1,3-butadiene, for example, using data on biomarkers in exposed Czech workers [1]. For this study, an extensive range of biomarkers of exposure and response was assessed, including: polymorphisms in metabolizing enzymes; urinary concentrations of several metabolites of 1,3-butadiene; hemoglobin adducts; HPRT mutations in T-lymphocytes; chromosomal aberrations by FISH and conventional staining procedures; sister chromatid exchanges. Exposure levels were monitored in a comprehensive fashion. For risk assessment purposes, these data need to be considered in the context of how they inform the MoA for leukemia, the tumor type reported to be increased in synthetic rubber workers exposed to 1,3-butadiene. Also, for the HRF it is necessary to establish key events for a MoA in rodents for the induction of tumors by 1,3-butadiene. There is clearly a species difference in sensitivity to tumor induction, with mice being much more sensitive than rats; key events need to explain this difference. For butadiene, the MoA is DNA-reactivity and subsequent mutagenicity and so following the EPA's cancer guidelines, a linear extrapolation is used from the point of departure (POD), unless additional data support a non-linear extrapolation. For the present case, the human bioindicator data are not informative as far as dose-response characterization is concerned. Mouse chromosome aberration data for in vivo exposures might be used for establishing a POD, with linear extrapolation from this POD. The available cytogenetic data from rodent studies appear to be sufficiently extensive and consistent for this to be a viable approach. This approach of using MoA and key events to establish the human relevance can lead to the development of specific informative bioindicators of response that can be used as surrogates to predict the shape of the tumor dose response curve at low doses. Truly informative predictors of tumor responses should be able to provide estimates of human tumor frequencies at low, environmental exposures to 1,3-butadiene.
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PMID:Cancer risk assessment for 1,3-butadiene: data integration opportunities. 1664 96

The extracellular matrix (ECM), the product of stromal cells, is now thought to make a dynamic network in tissues. Stromal cells can support other cells not only by direct contact but also via this ECM network. The regulated turnover and remodeling of ECM needs both ECM degrading enzymes named matrix metalloproteinases (MMPs) and their inhibitors called tissue inhibitors of metalloproteinases (TIMPs). Through an understanding of their molecular structure, the nature of the enzymic activity of MMPs and the inhibitory action of TIMPs against MMPs have been well elucidated. Considering their potent inhibitory action against MMPs, TIMPs are thought to play an important role in maintaining ECM. However, other unique functions of TIMPs have been reported, such as erythroid potentiating activity, cell growth-promoting activity, embryogenesis-stimulating activity, steroidogenesis-stimulating activity and so on. This review covers this new field, and discusses what role TIMPs can play in controlling life. In the second part, we briefly introduce our recent date on TIMPs and hematopoiesis. Because TIMPs have a dual function, i.e. a potent inhibitory action against MMPs and cell growth promoting action, TIMPs are good candidates for tissue fibrosis. Our recent measurements of TIMP-1 and TIMP-2 levels using serum and plasma from patients with platelet number disorders and cultured medium from various leukemia cell lines, shows that platelets are a rich source of TIMPs and that TIMP-1 is secreted in large amounts by megakaryoblastic- and erythro-leukemia cell lines. Proliferation of bone marrow fibroblasts can be stimulated by TIMP-1 and TIMP-2. Taken together, TIMPs might be one of the important factors for the process of myelofibrosis in some pathological conditions.
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PMID:Multiple functions of tissue inhibitors of metalloproteinases (TIMPs): new aspects in hematopoiesis. 1680 Oct 65

The dose-response assessment of the association between 1,3-butadiene (BD) and leukemia mortality among workers in the North American synthetic rubber industry is explored. Analyses are based on the most recent University of Alabama at Birmingham epidemiological study and exposure estimation. The U.S. EPA Science Advisory Board recommendations of using the most recent data and giving consideration to peak exposures to BD have been followed. If cumulative BD ppm-years is to be used as the predictor of the leukemia rate ratio, then the performance of that predictor is statistically significantly improved if the slope in the predictor is estimated with age and the cumulative number of BD peaks (where a BD peak is any exposure, regardless of duration, to a BD concentration above 100 ppm) added as categorical covariates. After age and the cumulative number of BD peaks are incorporated as categorical covariates in the Poisson regression model, the estimated concentration (EC(001)) corresponding to an excess risk of 0.001 as a result of continuous environmental exposure is 11.2 ppm; however, the estimated slope for BD cumulative ppm-years in the linear rate ratio for leukemia used to derive this EC(001) is not statistically significantly different from zero. Sensitivity analyses using alternative models indicate either essentially no risk or estimated EC(001) values of 9 and 77 ppm. Analyses suggesting the absence of a statistically significant low-dose risk versus cumulative BD ppm-years are presented. Sensitivity analyses of other malignant neoplasms of lymphatic and hematopoietic tissue (specifically, lymphoid and myeloid neoplasms) resulted in conclusions about the dose-response modeling methodology that were supportive of the methodology used for leukemia.
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PMID:Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective. 1687 50

To investigate the biological activity of various polyunsaturated fatty acids (PUFAs) on the allergic reaction, we examined the effects of six PUFAs and two saturated fatty acids on calcium response and degranulation from rat basophilic leukemia (RBL-2H3) cells. Between 20 and 40 microM of six PUFAs (omega-6 series: arachidonic acid [AA, C20:4], gamma-linolenic acid [gamma-LN, C18:3] and linoleic acid [LA, C18:2]; omega-3 series: alpha-linolenic acids [alpha-LN, C18:3] and eicosapentaenoic acid [EPA, C20:5]; and omega-9 series: oleic acid [OLE, C18:1]), or two saturated fatty acids (stearic acid [STA, C18:0] and arachidic acid [AD, C20:0]) were used to examine the effects on calcium response and degranulation from RBL-2H3 cells. Calcium response was monitored using the fluorescent calcium indicator fura-2, while degranulation was monitored by measuring histamine release from the cells. Three omega-6 PUFAs (AA, alpha-LN and LA) dose-dependently increased the cytosolic free-calcium concentration and histamine release from RBL-2H3 cells. This phenomenon was specific to the omega-6 PUFAs, the omega-3 PUFAs (alpha-LA and EPA), omega-9 PUFA (OLE) and the saturated fatty acids (STA and AD) had no effect. The increase in the cytosolic free-calcium concentration caused by the omega-6 PUFAs depended on the existence of external calcium, cell viability and the cellular IP(3) levels remained unchanged throughout the experiment. These results suggest that omega-6 PUFAs work as direct mediators of calcium signaling pathways in RBL-2H3 cells.
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PMID:Effects of polyunsaturated fatty acids on calcium response and degranulation from RBL-2H3 cells. 1717 88

Besides its matrix metalloproteinases inhibitory activity, TIMP-1 exhibits other biological activities such as cell survival and proliferation. The intracellular signalling pathway elicited by TIMP-1 begins to be elucidated. We have shown previously that the caspase-3 and the p38alpha MAP kinase were activated during TIMP-1-induced UT-7 cells erythroid differentiation. In this study, we demonstrated that TIMP-1 differentiating effect can be extended to the IL-3-dependent myeloid murine 32D cell line and human erythroid progenitors derived from cord blood CD34(+) cells. By performing small interfering RNA transfection and using chemical inhibitors, we evidenced that caspase-3 was involved in TIMP-1 differentiating effect. We then identified the MEKK1 kinase as a caspase-3 substrate and demonstrated that the MEKK1/MEK6/p38alpha pathway was activated downstream the caspase-3 in TIMP-1-induced hematopoietic differentiation.
Leukemia 2007 Apr
PMID:Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38alpha pathway. 1730 22


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