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)

In rat basophilic leukemia cells (2H3), a tumor analog of mast cells, the aggregation of IgE receptors results in histamine secretion and the increase in histidine decarboxylase activity which synthesizes histamine. Using inhibitors of protein kinases C, we studied the relationships between these events and protein kinase C which is activated by antigens. Histamine release is suppressed by inhibitors of protein kinase C, staurosporine, K252-a and H-7, in this decreasing order of effectiveness; and the IC50 values are 1.5 nM, 29.9 nM and 3.8 microM, respectively. The changes in the intracellular Ca concentration monitored by fura-2 fluorescence is not modified by staurosporine, although the histamine response is suppressed. Meanwhile, the increase of histidine decarboxylase was abolished by inhibitors of protein kinase C; staurosporine was the strongest, K-252a of moderate activity and H-7, the weakest, having IC50 values of 0.8 nM, 100 nM and 11.5 microM, respectively. The inhibitors of protein kinase C suppress both histamine secretion and synthesis. Therefore, the histamine synthesis may be stimulated via activation of protein kinase C to supplement the released histamine.
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PMID:Effects of inhibitors of protein kinase C on the release and synthesis of histamine in rat basophilic leukemia cells (2H3). 138 Oct

Novel derivatives of K-252a, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl- 8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibe nzo[a,g]-cycloocta[cde]trinden-1-one, an inhibitor of protein kinases and calmodulin-dependent phosphodiesterase, were synthesized and evaluated for their antitumor activity in vitro and in vivo. Of ten derivatives tested, four were active against the P388 murine leukemia i.p.-i.p. system, although K-252a was inactive. Among these derivatives, KT6124 was selected for further biological evaluation studies because its efficacy was the highest. KT6124 was also active against sarcoma 180 and B16 melanoma. It exerted a relatively broad spectrum of antiproliferative activity against 20 human tumor cell lines in vitro. To determine the mechanism(s) of action underlying the antitumor activity of KT6124, we tested the drug for inhibition of protein kinases, including Ca(2+)- and phospholipid-dependent protein kinase (PKC), in intact A431 human epidermoid carcinoma cells in comparison with the PKC-inhibitory activity of K-252a. KT6124 did not antagonize the action of phorbol 12-myristate 13-acetate (PMA) in A431 cells, whereas K-252a did, suggesting that KT6124 may not act on protein kinases in the cells. The interaction of KT6124 with DNA in living cells was examined by the alkaline elution method. KT6124 apparently exhibited DNA scission both dose- and time-dependently in the target cells. The DNA breakage was dependent on proteinase K treatment, suggesting its possible interaction with DNA-related enzyme(s). These results indicate that KT6124 exerts antitumor activity by acting on DNA or on DNA-related enzyme(s) in tumor cells rather than via the inhibition of protein kinases.
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PMID:Antitumor effect of KT6124, a novel derivative of protein kinase inhibitor K-252a, and its mechanism of action. 153 71

Effects of okadaic acid (OA) and calyculin-A (CL-A), selective inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A), on the release of serotonin from the rat basophilic leukemia cell line (RBL-2H3) were investigated. Both OA and CL-A induced the long-lasting release of serotonin in an extracellular Ca(2+)-independent manner. CL-A did not increase intracellular Ca2+ concentration in the fura-2-loaded cells. CL-A was 100-fold more potent than OA in inducing the release, suggesting that PP1 is a dominant protein phosphatase in regulating RBL-2H3 cells. The CL-A-induced release of serotonin was completely inhibited by the nonselective protein kinase inhibitors, staurosporine and K-252a. CL-A induced phosphorylation of several cellular proteins in RBL-2H3 cells, which could be inhibited by staurosporine. These findings suggest that the release of serotonin is subject to tonic, Ca(2+)-independent, inhibition by PP1 in RBL-2H3 cells.
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PMID:Protein phosphatase inhibitors induce the release of serotonin from rat basophilic leukemia cells (RBL-2H3). 816 51

UCN-01 (7-hydroxy-staurosporine) is a potent and selective inhibitor of protein kinase C (PKC), one of several protein kinases examined. UCN-01 itself was shown to exhibit antitumor activity in vitro and in vivo in oncogene-activated human and murine tumor cell lines. Since the mechanism(s) of action of UCN-01 is thought to be different from those of alkylating agents, including mitomycin C (MMC), we tested the combined effect of UCN-01 with MMC on human epidermoid carcinoma A431 cells. UCN-01 potentiated the antiproliferative activity of MMC and yet it did not affect the growth of the cells in vitro. However, other nonselective protein kinase inhibitors, such as staurosporine, K-252a, KT6124 (a derivative of K-252a) and H7, did not enhance the activity of MMC. Isobologram analysis revealed that the interaction of UCN-01 with MMC was synergistic in its antiproliferative activity. A DNA histogram of A431 cells treated with both UCN-01 and MMC showed a block in the cell cycle at the G1/S phase. However, a histogram of cells treated with UCN-01 or MMC alone showed a G1 or a G2M block, respectively. The combined effect of UCN-01 with MMC was further examined in vivo in xenografted A431 cells in nude mice. The combination of both drugs in a single i.v. injection exhibited greater antitumor activity than MMC and UCN-01 alone (P < 0.01). This synergistic antitumor effect was also confirmed in two other solid tumor cell lines, i.e. human xenografted colon carcinoma Co-3 and murine sarcoma 180. The same was observed in the i.v.-inoculated P388 leukemia model, in which we saw an increased lifespan of mice when UCN-01 was combined with MMC. These results suggests the feasibility of using UCN-01 in clinical oncology, especially in combination with alkylating agents such as MMC. In addition, this combination therapy might be a novel chemotherapeutic approach to MMC-insensitive tumors in clinical trials.
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PMID:Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. 850 Feb 22

Thrombopoietin (TPO) is a recently cloned growth and differentiation factor implicated in megakaryocytopoiesis. Here, we show that TPO, interleukin-3 (IL-3) and, at least in short-term assays, also interferon gamma (IFN gamma) induced proliferation in acute myeloid leukemia (AML-M7)-derived M-07e cells. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway was activated after stimulation with any of the three cytokines. Thus, the TPO-receptor (TPO-R) MPL was tyrosine phosphorylated after a short-term stimulation with TPO, followed by tyrosine phosphorylation of STAT 3 and STAT 5, but not of STAT 1. IL-3 and IFN gamma induced phosphorylation of STAT 5 or STAT 1, respectively, without affecting the other STATs. As STATs are thought to regulate proliferation by modulating expression of inhibitors of cyclin-dependent kinases (Cdk), we analyzed p21 and p27 expression after stimulation with TPO or IL-3. In contrast to the constitutively low p21 expression, p27 mRNA levels were high in synchronized, cytokine-deprived cells in G0/1 phase. Stimulation with TPO or IL-3 induced a rapid decrease of p27 mRNA. The phosphorylation cycle of the retinoblastoma protein (Rb) was inversely correlated with the level of p27 mRNA. Hyperphosphorylation of Rb was detectable 9 h after onset of stimulation, concomitantly with the decrease of p27 mRNA and shortly before transition of the cells into S phase. As phosphorylation of Rb is a key event for transition of cells into S phase, our observations support the notion of p27 being an important regulator during cytokine-induced proliferation. Whether the JAK/STAT pathway is directly involved in p27 expression or not, remains to be elucidated. The JAK inhibitor AG-490 blocked cytokine-induced STAT 5 phosphorylation and proliferation of M-07e cells in a dose-dependent manner. Although these data indicate a role for the JAK/STAT pathway in cytokine-induced proliferation, a direct influence on the p27 mRNA downregulation has to be confirmed. The second major effect of TPO, polypoidization, could not be observed in M-07e cells. Even long-term culture with TPO did not induce endomitosis in these cells. However, polyploidization could be brought about by the kinase inhibitor K-252a. After 3 days of exposure to this reagent, 17% of the originally mononucleated cells contained two to five nuclei. K-252a-induced polykaryon formation was not preceded by STAT 5 phosphorylation. Thus, K-252a did not mimic TPO stimulation at the early steps of the signaling chain. Taken together, our experiments confirm a role for the JAK/STAT pathway in cytokine-induced proliferation; TPO and IL-3 induce downregulation of the Cdk inhibitor p27, hyperphosphorylation of Rb and subsequently transition of the cells into S phase; the kinase inhibitor K-252a induces polyploidization of M-07e cells, but this effect is independent of STAT 5 phosphorylation.
Leukemia 1998 Oct
PMID:Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e. 976 6

Genetic findings have suggested that neuregulin-1 (Nrg1) and its receptor v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) may play a role in neuropsychiatric diseases. However, the downstream signaling events and relevant phenotypic consequences of altered Nrg1 signaling in the nervous system remain poorly understood. To identify small molecules for probing Nrg1-ErbB4 signaling, a PC12-cell model was developed and used to perform a live-cell, image-based screen of the effects of small molecules on Nrg1-induced neuritogenesis. By comparing the resulting phenotypic data to that of a similar screening performed with nerve growth factor (NGF), this multidimensional screen identified compounds that directly inhibit Nrg1-ErbB4 signaling, such as the 4-anilino-quinazoline Iressa (gefitinib), as well as compounds that potentiate Nrg1-ErbB4 signaling, such as the indolocarbazole K-252a. These findings provide new insights into the regulation of Nrg1-ErbB4 signaling events and demonstrate the feasibility of using such a multidimensional, chemical-genetic approach for discovering probes of pathways implicated in neuropsychiatric diseases.
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PMID:Chemical genetics identifies small-molecule modulators of neuritogenesis involving neuregulin-1/ErbB4 signaling. 2049 71