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)

Herbimycin A, a selective inhibitor of tyrosine kinase activity, induced differentiation of leukemia cells isolated from Philadelphia chromosome-positive chronic myelogenous leukemia patients. However, it did not induce differentiation of leukemia cells from acute myelogenous leukemia patients, although these cells could be induced to differentiate by treatment with appropriate compounds. A selective inhibitor of tyrosine kinase might be useful in chemotherapy of Philadelphia chromosome-positive leukemia.
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PMID:Control of growth and differentiation of Philadelphia chromosome-positive leukemia cells by tyrosine kinase inhibitors. 130 24

Herbimycin A, a benzoquinoid ansamycin antibiotic, was demonstrated to decrease intracellular phosphorylation by protein tyrosine kinase (PTK). In Philadelphia chromosome (Ph1)-positive leukemias such as chronic myelogenous leukemia (CML) and Ph1-positive acute lymphoblastic leukemia (ALL), both of which express bcr-abl fused gene products (P210bcr-abl or P190bcr-abl protein kinase) with augmented tyrosine kinase activities, herbimycin A markedly inhibited the in vitro growth of the Ph1-positive ALL cells and the leukemic cells derived from CML blast crisis. However, the same dose of herbimycin A did not inhibit in vitro growth of a broad spectrum of Ph1-negative human leukemia cells, and several other protein kinase antagonists also displayed no preferential inhibition. Furthermore, we demonstrated that herbimycin A has an antagonizing effect on the growth of transformed cells by a transfection of retroviral amphotrophic vector expressing P210bcr/abl into a murine interleukin (IL)-3-dependent myeloid FDC-P2 cell line. This inhibition was abrogated by the addition of sulfhydryl compounds, similar to the reaction previously described for Rous sarcoma virus transformation. The inhibitory effect of herbimycin A on the growth of Ph1-positive cells was associated with decreased bcr/abl tyrosine kinase activity, but no decrease of bcr-abl mRNA and protein, suggesting that the inactivation of bcr-abl tyrosine kinase activity by herbimycin A may be induced by its binding to the bcr-abl protein portion that is rich with sulfhydryl groups. The present study indicates that herbimycin A is a beneficial agent for the investigation of the role of the bcr-abl gene in Ph1-positive leukemias and further suggests that the development of agents inhibiting the bcr-abl gene product may offer a new therapeutic potential for Ph1-positive leukemias.
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PMID:Effect of herbimycin A, an antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell proliferations: abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein P210bcr/abl and preferential inhibition on Ph1-positive leukemia cell growth. 151 46

Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some tyrosine kinases, including v-abl. The mouse megakaryoblastic cell line C1 expresses v-abl protein at high levels. Herbimycin A at about 20 ng/ml caused 50% inhibition of growth of C1 cells but at 100 ng/ml scarcely affected the growth of another mouse leukemia cell line, M1 cells, or of normal bone marrow cells. Injection of 10(6) C1 cells into nude mice resulted in death of all the mice within 30 days. Administration of herbimycin A significantly enhanced the survival of mice inoculated with C1 cells but scarcely affected the survival of mice inoculated with M1 cells. These results suggest that herbimycin A and/or related compounds may be useful for treatment of some types of leukemia in which tyrosine kinase activity is implicated as a determinant of the oncogenic state.
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PMID:Herbimycin A, an inhibitor of tyrosine kinase, prolongs survival of mice inoculated with myeloid leukemia C1 cells with high expression of v-abl tyrosine kinase. 161 78

We investigated the effect of recombinant human interleukin-4 (rhIL-4) on the in vitro growth of human leukemia cells in liquid culture and 3H-thymidine incorporation and found inhibitory effects on the growth of leukemic cells from patients with Ph1-positive acute lymphoblastic leukemia (Ph1 ALL) and three Ph1 ALL cell lines. However, no inhibitory effects were seen in Ph1-positive leukemic cell lines derived from patients with chronic myelogenous leukemia in blast crisis and various types of Ph1-negative leukemia cells, including B-lineage leukemia cells. In a flow cytometry assay of IL-4 receptor (IL-4R), all three Ph1-positive ALL cell lines showed the presence of IL-4R on their cell surfaces, and the IL-4-dependent inhibition on the growth of Ph1-positive ALL cells was abrogated by the addition of either monoclonal or polyclonal antibodies against rhIL-4. Other cytokines, including IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and IL-6, showed no inhibitory effects on the growth of Ph1-ALL cells, but tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-alpha, -beta, and -gamma displayed slight inhibitory effects in a high concentration. The growth inhibition induced by rhIL-4 in the Ph1-positive ALL cells was not abrogated by the addition of antibodies against either IFN-gamma or TNF-alpha. Furthermore, these cells showed no significant production of IFN-alpha, -beta, or -gamma or TNF-alpha after exposure to rhIL-4, thus indicating that the growth inhibition of Ph1-positive ALL cells by rhIL-4 is not associated with IL-4-stimulating production of these factors. rhIL-4 caused significant inhibition of the tyrosine kinase activity in these Ph1-positive ALL cells, similar to Herbimycin A, an inhibitor of tyrosine kinase that inhibited the tyrosine kinase activity in these cells. Our finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibilities for patients with Ph1-positive ALL.
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PMID:Inhibitory effect of interleukin-4 on the in vitro growth of Ph1-positive acute lymphoblastic leukemia cells. 188 23

Herbimycin A, a benzoquinonoid ansamycin antibiotic, is found to reduce intracellular phosphorylation by tyrosine protein kinase. The human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. When K562 cells are induced to undergo erythroid differentiation by hemin, reduction in the intracellular level of tyrosine phosphorylation occurs. In order to understand the relationship between induction of differentiation and reduction of tyrosine phosphorylation by the c-abl gene product, the effect that herbimycin A, a selective inhibitor of intracellular tyrosine kinase activity, exerts on the differentiation of K562 cells was examined. Reduction of tyrosine phosphorylation in K562 cells by herbimycin A was observed within 1 h. Noncytotoxic concentrations of herbimycin A induced erythroid differentiation of K562 cells but not of murine erythroleukemia 745A cells. The other human myeloid leukemia cell lines (HL-60, THP-1, and U937) tested were not induced to undergo cell differentiation by this antibiotic. Herbimycin A and the other well-known inducers such as hemin, butyric acid, Adriamycin, and 1-beta-D-arabinofuranosylcytosine had additive or more than additive effects on induction of erythroid differentiation of K562 cells. With respect to inhibition of cell growth, the sensitivity of K562 cells to herbimycin A was highest in the human leukemia cell lines we tested. Noncytotoxic concentrations of herbimycin enhanced the antiproliferative effect of Adriamycin or 1-beta-D-arabinofuranosylcytosine on K562 cells. Combination therapy with herbimycin A and its derivatives may be considered for use in the treatment of some types of leukemia where tyrosine kinase activities are implicated as determinants of the oncogenic state.
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PMID:Induction of erythroid differentiation of K562 human leukemic cells by herbimycin A, an inhibitor of tyrosine kinase activity. 291 Apr 52

Herbimycin A, a benzoquinonoid anasamycin antibiotic, preferentially inhibited the in vitro growth of Ph1-positive leukemia cell lines. On the other hand, genistein, which was developed as an inhibitor of receptor-type tyrosine kinase, and other protein kinase inhibitors showed no selective inhibition of Ph1-positive leukemia cell growth. Herbimycin A also displayed an abrogative effect on the transformation of murine hematopoietic cells by transfection with a bcr/abl oncoprotein-expressing retroviral vector. The antitumor action of herbimycin A on Ph1-positive leukemia cells is related to an inhibition of activity of bcr/abl protein tyrosine kinase and a subsequent reduction of the constitutive phosphotyrosyl proteins, however, the antibiotic has no effect on the expression of bcr/abl mRNA and oncoprotein. Therefore, herbimycin A may provide an important insight into the oncogenic action of bcr/abl oncoprotein and the future development of oncoprotein-targeted therapeutic agents.
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PMID:Effect of herbimycin A, an inhibitor of tyrosine kinase, on protein tyrosine kinase activity and phosphotyrosyl proteins of Ph1-positive leukemia cells. 751 Nov 93

12-O-Tetradecanoylphorbol 13-acetate (TPA) induces rapid changes in the morphology of the human megakaryoblastic leukemia cell line, MEG-01, as well as changes in adhesion and megakaryocytic differentiation. To investigate the signal transduction pathway of these three phenomena, we studied the effect of herbimycin A, an inhibitor of tyrosine kinase (TK) and the effects of calphostin C, a specific inhibitor protein kinase C (PKC) on TPA treated MEG-01 cells. Both herbimycin A and calphostin C inhibited all three TPA-induced phenomena, suggesting that both pathways are required for these phenomena. Herbimycin A but not calphostin C blocked the tyrosine phosphorylation of cellular proteins. Immunohistochemical staining of PKC using an anti-PKC monoclonal antibody showed that herbimycin A did not interfere with the translocation and subsequent down regulation of PKC induced by TPA, suggesting that the TPA-induced effect on PKC (translocation and probably its activation) is not dependent on TK. Induction of c-fos and c-jun expression by TPA was inhibited by both herbimycin A and calphostin C, suggesting that both PKC and TK pathways are necessary for the induction of the TPA-induced transcription factor AP1, which is a known TPA-inducible early immediate gene product. Taken together, our results show that the tyrosine kinase signal transduction system as well as the PKC pathway is indispensable for the TPA-induced phenomena of morphologic change, cell attachment, early immediate gene expression, and lineage-specific phenotypic expression in the MEG-01 cell line.
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PMID:Herbimycin A inhibits phorbol ester-induced morphologic changes, adhesion, and megakaryocytic differentiation of the leukemia cell line, MEG-01. 753 28

The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1-positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia.
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PMID:Treatment of Philadelphia-chromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosine kinase activity inhibitor. 786 Jan 43

Herbimycin A, a benzoquinoid ansamycin antibiotic, has been shown to reverse the oncogenic phenotype of p60v-src transformed cells because of the inhibition of src protein tyrosine kinase. We previously demonstrated that herbimycin A displayed antitumor activity on the in vitro growth of Philadelphia chromosome-positive leukemia cells and BCR/ABL-transfected murine hematopoietic FDC-P2 cells through the inhibition of BCR/ABL protein tyrosine kinase. In this study, the transformed FDC-P2 cells were demonstrated to be tumorigenic in syngeneic DBA/2 mice. The intraperitoneal (i.p.) injection of the transformed tumor cells into DBA/2 mice induced infiltrations of abdominal organs, and then all of the mice died within time periods proportional to the cell numbers of inoculation. In mice that received an i.p. inoculation with greater than 1 x 10(5) cells, in vivo administration of herbimycin A by i.p. injection inhibited tumor formation and significantly prolonged survival time, and further, in mice inoculated with 1 x 10(4) cells, herbimycin A completely suppressed the in vivo growth of transformant FDC-P2 cells and brought about a complete remission. The present study revealed the in vivo efficacy of herbimycin A in mice bearing BCR/ABL-transfected cells.
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PMID:In vivo antitumor activity of herbimycin A, a tyrosine kinase inhibitor, targeted against BCR/ABL oncoprotein in mice bearing BCR/ABL-transfected cells. 796 14

Herbimycin A, a benzoquinonoid anasamycin antibiotic, has been shown to reserve the oncogenic phenotypes of p60v-src transformed cells by the virtue of the inhibition of src protein tyrosine kinase. Furthermore, we previously demonstrated that herbimycin A displayed the antitumor activity on Ph1-positive leukemia cells and bcr/abl oncoprotein-associated transformed murine hematopoietic cells with the transfection of a retroviral vector expressing bcr/abl. Herbimycin A showed preferential inhibition on the in vitro growth of Ph1-positive leukemia cells and bcr/abl oncoprotein-associated murine hematopoietic cells through the inhibition of bcr/abl tyrosine kinase activity and the reduction of subsequent phosphotyrosyl proteins. Recently, from the view of investigating the oncogenic significance or of developing a future clinical application in malignancies, several developing agents targeted against oncoprotein have been tried. We reviewed the present progress in the mechanism of oncoprotein-targeted antitumor effects and focused on herbimycin A-induced antitumor activity on Ph1-positive leukemia cells.
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PMID:New insight into oncoprotein-targeted antitumor effect: herbimycin A as an antagonist of protein tyrosine kinase against Ph1-positive leukemia cells. 816 36


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