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)

In RBL-2H3 rat basophilic leukemia cells, Fc epsilon R1 crosslinking by multivalent antigen stimulates phosphatidylinositol (PI) turnover and Ca2+ influx and causes functional responses that include secretion, membrane ruffling and actin polymerization. Here, we show that the tyrosine kinase inhibitor, genistein, inhibits antigen-induced PI turnover, determined from assays of 1,4,5-inositol trisphosphate production, and impairs receptor-mediated secretion, ruffling and actin polymerization. Genistein has little effect on several functional responses to stimuli that bypass PI hydrolysis (ionomycin-induced secretion, phorbol ester-induced ruffling) but it inhibits phorbol ester-induced actin polymerization. These data implicate a common tyrosine kinase-dependent event, most likely the activation of phospholipase C gamma, in the Fc epsilon R1-mediated stimulation of PI turnover, secretion and ruffling. There may be additional tyrosine kinase-mediated events in the actin assembly pathway.
 ...
PMID:Tyrosine kinase-dependent phosphatidylinostiol turnover and functional responses in the Fc epsilon R1 signalling pathway. 183 80

Genistein, an in vitro inhibitor of topoisomerase II and tyrosine kinases, suppressed growth and induced differentiation in HL-205 cells, a clonal population of the human promyelocytic HL-60 leukemia cells, and in K-562-J cells, a clonal population of the human erythroid K-562 leukemia cells. Maturing HL-205 cells acquired either granulocytic or monocytic markers, namely, reactivity with the murine OKM1 monoclonal antibody, expression of nitroblue tetrazolium dye reduction, and staining for nonspecific esterase. The maturing K-562-J cells stained with benzidine, which indicates the presence of hemoglobin, an erythroid maturation marker. Although the acquisition of the maturation markers in both HL-205 and K-562-J cells was time dependent up to 6 days, the kinetics of this induction differed between the two cell types. Despite the in vitro inhibitory effect of genistein, treatment of either HL-205 or K-562-J cells with 150 micrograms/ml genistein for up to 16 h did not alter topoisomerase II activity (as determined by the unknotting assay) in their nuclear extracts. Analysis with the anti-phosphotyrosine PY-20 murine monoclonal antibody indicated that treatment of K-562-J cells with genistein decreased the reactivity of the antibody with two of the cellular proteins. However, no reactivity with the PY-20 antibody was detected in untreated or genistein-treated HL-205 cells. An early event in the HL-205 and K-562-J cells, occurring after only 1 h of treatment with 30-200 micrograms/ml genistein, was the induction of DNA damage as measured by an alkaline elution assay. This damage may be a contributing factor in the genistein-induced cell differentiation in the HL-205 and K-562-J cells.
 ...
PMID:Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. 215 95

Some lines of colon cancer cells are forced to undergo differentiation by 12-O-tetradecanoylphorbol-13-acetate (TPA). The increases in activities of both protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) have been reported to be associated with the TPA-induced differentiation of HL-60 leukemia cells. In the present study, a 2-fold increase in PTP activity was observed in SW620 human colon cancer cells after 30 min of TPA treatment; a maximal level (4- to 5-fold) was reached at 60 min and continued for more than 6 hr. In addition, two TPA-induced differentiated characteristics, morphological alteration and release of cellular surface proteoglycan, were effectively blocked by PTP inhibitors, such as sodium orthovanadate (50 microM), zinc chloride (100 microM), and iodoacetate (250 microM), but not by the protein serine/threonine phosphatase inhibitor okadaic acid (20 nM). On the other hand, although TPA induced a transient slight increase in PTK activity (1.4-fold) at 60 min, four PTK inhibitors (genistein, herbimycin A, tyrphostin-23 and quercetin) had different effects on the TPA-induced release of cell surface proteoglycan. Genistein (60 microM) potentiated this process, but in contrast, quercetin (45 microM) could partially inhibit the TPA effect. Taken together, these observations suggest that both PTP and PTK activities were increased in SW620 cells in response to TPA; however, the activation of PTP seems to be preferentially required for the TPA-induced differentiation of SW620 human colon cancer cells.
 ...
PMID:Preferential requirement for protein tyrosine phosphatase activity in the 12-O-tetradecanoylphorbol-13-acetate-induced differentiation of human colon cancer cells. 748 37

Binding of circulating cells to endothelium is mediated by recognition between endothelial adhesion molecules and their counter-receptors. The beta 2 integrins are a group of adhesion molecules, mainly expressed on leukocytes, that mediate intercellular binding by recognizing their counterparts on endothelial cells, among others ICAM-1. In this study we have studied the regulation of this interaction in myelomonocytic cells treated with genistein, a tyrosine kinase inhibitor with several other biological functions. We show that genistein upregulates the surface expression of the beta 2-integrins in the monoblastic THP-1 and to a lesser extent in the promyelocytic HL-60 leukemia cell lines. This upregulation leads to an increase in the adherence of THP-1 cells to ICAM-1. Genistein also modulates the expression of ICAM-1 on endothelial cells by potentiating the upregulating effect of TNF and IFN-gamma. Genistein may thus enhance intercellular binding by affecting both the endothelium and the circulating cells.
 ...
PMID:Genistein enhances the ICAM-mediated adhesion by inducing the expression of ICAM-1 and its counter-receptors. 752 Nov 64

B-cell precursor (BCP) leukemia is the most common form of childhood cancer and the second most common form of acute leukemia in adults. Human BCP leukemia was treated in a severe combined immunodeficient mouse model by targeting of the tyrosine kinase inhibitor Genistein (Gen) to the B cell-specific receptor CD19 with the monoclonal antibody B43. The B43-Gen immunoconjugate bound with high affinity to BCP leukemia cells, selectively inhibited CD19-associated tyrosine kinases, and triggered rapid apoptotic cell death. At less than one-tenth the maximum tolerated dose more than 99.999 percent of human BCP leukemia cells were killed, which led to 100 percent long-term event-free survival from an otherwise invariably fatal leukemia. The B43-Gen immuno-conjugate might be useful in eliminating leukemia cells in patients who have failed conventional therapy.
 ...
PMID:Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. 753 65

Genistein is an inhibitor of the enzymes protein tyrosine kinase and topoisomerase-II. It induces G2-phase arrest in human Jurkat and murine P388 leukemia cells at concentrations at which it is also cytotoxic. The effects of genistein have been investigated on Jurkat and P388 leukemia sublines that manifest multidrug resistance. Cells that possess altered topoisomerase-II activity ("atypical" multidrug resistance) are resistant to both the G2 phase-arresting and cytotoxic effects of genistein. The ability of genistein to impede progression through the cell cycle and kill cells is similar to that of amsacrine, a classical topoisomerase-II poison. This result identifies topoisomerase-II rather than tyrosine kinase activity as the target of genistein-mediated cytotoxicity and G2-phase arrest.
 ...
PMID:Comparison of the effects of genistein and amsacrine on leukemia cell proliferation. 791 50

Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinases. We analyzed the effects of genistein on in vitro growth, cell-cycle progression and chromatin structure of Jurkat cells, a T-cell leukemia line with a constitutively increased tyrosine phosphorylation pattern. Exposure of in vitro cultured Jurkat cells to genistein resulted in a dose-dependent, growth inhibition. Cell-cycle analysis of genistein-treated cells revealed a G2/M arrest at low genistein concentrations (5-10 micrograms/ml), while at higher doses (20-30 micrograms/ml) there was also a perturbation in S-phase progression. The derangements in cell-cycle control were followed by apoptotic death of genistein-treated cells. Immunocytochemical analysis of cells stained with a FITC-conjugated anti-phosphotyrosine monoclonal antibody showed that 30 micrograms/ml genistein effectively inhibit tyrosine kinase activity in cultured Jurkat cells. Our results indicate that the natural isoflavone genistein antagonizes tumor cell growth through both cell-cycle arrest and induction of apoptosis and suggest that it could be a promising new agent in cancer therapy.
 ...
PMID:The natural tyrosine kinase inhibitor genistein produces cell cycle arrest and apoptosis in Jurkat T-leukemia cells. 820 61

The natural isoflavone genistein inhibits the growth of a number of tumour cell lines in vitro. During investigations on the antiproliferative effects of genistein we observed that, with respect to direct cell counting, a tetrazolium (MTT) colorimetric assay consistently underestimated the growth inhibitory activity of the substance. Cell proliferation was markedly inhibited by genistein in three tumour cell lines (MCF-7, human breast tumour; Jurkat cells, human T-cell leukaemia; L-929, mouse transformed fibroblasts) when cell number was evaluated by direct counting, whereas a 72-h MTT assay failed to reveal any growth-inhibitory effect. Cell cycle analysis by propidium iodide staining and flow-cytometry revealed a G2/M cell cycle arrest after genistein treatment. Genistein-treated cells displayed an increase in cell volume and in mitochondrial number and/or activity, as revealed by enhanced formazan generation and increased uptake of the vital mitochondrial dye rhodamine 123. These results suggest that alterations in cell cycle phase redistribution of tumour cells by genistein may significantly influence mitochondrial number and/or function and, consequently, MTT reduction to formazan. This may constitute an important bias in analysing the effects of genistein, and possibly other drugs that block the G2/M transition, on growth and viability of cancer cells in vitro by MTT assay.
 ...
PMID:Genistein inhibits tumour cell growth in vitro but enhances mitochondrial reduction of tetrazolium salts: a further pitfall in the use of the MTT assay for evaluating cell growth and survival. 821 51

Mouse leukemia Mm-A and Mm-S2 cells are subclones of mouse monocytic leukemia Mm cells, Mm-A cells having much higher leukemogenicity than Mm-S2 cells. The growth-inhibitory effects of several protein kinase inhibitors on leukemogenic Mm-A and non-leukemogenic Mm-S2 cells were examined. Most inhibitors of protein serine/threonine kinases inhibited the growth of Mm-A and Mm-S2 cells similarly, but some protein tyrosine kinase inhibitors exhibited differential inhibitory effects on Mm-A and Mm-S2 cells. Genistein inhibited growth of Mm-A cells more effectively than that of Mm-S2 cells, but another inhibitor of tyrosine kinase, herbimycin A, preferentially inhibited growth of non-leukemogenic Mm-S2 cells. Genistein induced or enhanced several differentiation markers of Mm-S2 cells, such as cell spreading, immunophagocytosis, nitroblue tetrazolium (NBT) reduction and lysozyme activity in a dose-dependent manner, but herbimycin A did not. Genistein was cytotoxic to Mm-A cells rather than inducing cell differentiation. Genistein has effects on several other cellular events as well as inhibition of tyrosine kinases. However, it effectively inhibited protein tyrosine phosphorylation in Mm-A cells and its decrease of tyrosine phosphorylation was closely associated with its inhibition of cell growth. Thus, a genistein-sensitive tyrosine kinase(s) may play an important role in the growth and/or survival of leukemogenic Mm-A cells.
 ...
PMID:Genistein exhibits preferential cytotoxicity to a leukemogenic variant but induces differentiation of a non-leukemogenic variant of the mouse monocytic leukemia Mm cell line. 841 97

Receptor and nonreceptor protein tyrosine kinases (PTKs) play a key role in the control of normal and neoplastic cell growth. The availability of PTK inhibitors prompted us to evaluate the effects of genistein, a natural inhibitor of PTKs, on in vitro colony formation by normal multilineage colony-forming units (CFU-Mix), erythroid bursts (BFU-E), granulocyte-macrophage colony-forming units (CFU-GM), long-term culture-initiating cells (LTC-IC) and acute myelogenous leukaemia colony-forming units (CFU-AML). Continuous exposure of normal marrow and blood mononuclear non-adherent cells, blood CD34+CD45RA- cells, and leukaemic blasts to increasing doses of genistein (1-100 microM) resulted in a statistically significant (P < or = 0.05) dose-dependent suppression of CFU-Mix, BFU-E, CFU-GM and CFU-AML growth. Regression analysis showed that growth inhibition was linearly related to genistein concentration. Genistein dose causing 50% inhibition (ID50) of CFU-AML was significantly lower compared to CFU-GM ID50 for marrow (19 v 32 microM, P < or = 0.017), unseparated blood (19 v 44 microM, P < or = 0.028) or CD34+CD45RA- blood (19 v 36, P < or = 0.04). Preincubation of leukaemic blasts with genistein (200 microM) for 1-2h confirmed that CFU-AML were significantly more sensitive than normal marrow and blood CFU-GM to genistein. Preincubation conditions which maximally suppressed leukaemic and normal colony growth spared a substantial percentage of marrow (29 +/- 4%) and blood (40 +/- 3%) LTC-IC. In conclusion, our data demonstrate that: (a) genistein strongly inhibits the growth of normal and leukaemic haemopoietic progenitors; (b) growth inhibition is dose- and time-dependent; (c) leukaemic progenitors are more sensitive than normal progenitors to genistein-induced growth inhibition; (d) genistein exerts a direct toxic effect on haemopoietic cells while sparing a substantial proportion of LTC-IC. The potent CFU-AML growth inhibition associated with the relative resistance of normal LTC-IC strongly supports the use of genistein for marrow purging.
 ...
PMID:Effect of the protein tyrosine kinase inhibitor genistein on normal and leukaemic haemopoietic progenitor cells. 865 72


1 2 3 4 Next >>