Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have demonstrated tamoxifen inhibition of the enzyme protein kinase C (PKC) in vitro. The aim of this study was to investigate the effects of tamoxifen on PKC function in intact human cells. As PKC activates the neutrophil oxidase mechanism the neutrophil was chosen as an experimental model to assess PKC-tamoxifen interaction in these experiments. Neutrophils from healthy volunteers were separated by centrifugation through Ficoll Hypaque. Two separate parameters of oxidase activation; oxygen consumption and reactive oxygen metabolite production were monitored by a Clark electrode chamber and luminol dependent chemiluminescence respectively. Neutrophil chemiluminescence was markedly stimulated by 4 Phorbol-12 myristate-13 acetate (PMA). This stimulation was inhibited by tamoxifen; IC50 = 6.1 +/- 1.6 microM (means +/- S.E.M.) N = 6. Neutrophil oxygen consumption was similarly stimulated by PMA and inhibited by tamoxifen. The tamoxifen inhibition was not due to cell toxicity as assessment of cell integrity by the exclusion of trypan blue and measurement of intracellular concentrations of ATP showed no significant differences before and after treatment. Tamoxifen also inhibited neutrophil chemiluminescence which was stimulated by oleoyl acetyl glycerol and mezerein excluding interaction with PMA as an explanation of its inhibitory effect. These results are consistent with tamoxifen inhibition of PKC function in intact human cells. This may be central to its antitumour action.
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PMID:Inhibition of protein kinase C mediated signal transduction by tamoxifen. Importance for antitumour activity. 379 Jan 65

Antiestrogens (tamoxifen, clomiphene and nafoxidine) were found to inhibit phospholipid/Ca2+-dependent protein kinase (PL/Ca-PK, or protein kinase C), whereas estrogens (estradiol and diethylstilbesterol) and the weakly estrogenic chlorotrianisene were inactive. Kinetic analysis indicated that the antiestrogens inhibited PL/Ca-PK competitively with respect to phosphatidylserine (Ki = 16-27 microM), but non-competitively with Ca2+ (Ki = 14-30 microM). Tamoxifen, but not diethylstilbesterol, also inhibited the phospholipid/Ca2+-dependent phosphorylation of various endogenous proteins from the total, solubilized fraction of the rat brain and ovary. Myosin light chain kinase, a calmodulin/Ca2+-dependent class of protein kinase, was similarly inhibited by tamoxifen; the drug, however, was without effect on cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It is suggested that PL/Ca-PK, by virtue of the hydrophobic interactions required for the enzyme activation, may represent a potential site of action for the lipophilic antiestrogens, in addition to the commonly recognized intracellular estrogen receptors.
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PMID:Effect of tamoxifen, a nonsteroidal antiestrogen, on phospholipid/calcium-dependent protein kinase and phosphorylation of its endogenous substrate proteins from the rat brain and ovary. 384 Mar 75

Recent studies have suggested that the triphenylethylene antiestrogen tamoxifen inhibits the proliferation in vitro of a substantial percentage of cell lines derived from adult high-grade gliomas, potentially acting through inhibition of the second messenger protein kinase C. These findings have formed the impetus for clinical trials of this agent in adults with malignant gliomas. However, it has previously remained uncertain whether tamoxifen has a similar inhibitory effect on the proliferation of pediatric high-grade gliomas, and whether low-grade gliomas, which constitute the majority of glial neoplasms in children, are also inhibited by this agent. To address these issues, the present study examined the effect of tamoxifen on proliferation and viability in a series of low-passage cell lines derived both from low-grade and high-grade pediatric gliomas. This agent was tested in three malignant gliomas, two pilocytic astrocytomas, two non-pilocytic low-grade astrocytomas, 1 mixed glioma, and 1 oligodendroglioma. Tamoxifen produced a dose-dependent inhibition of proliferation in two of the three malignant glioma cell lines and in each of the low-grade glioma cell lines with a 50% effective dose of approximately 3 micrograms/ml (5.4 microM), which is comparable to the IC50 for inhibition of PKC activity by this agent. No significant cytotoxicity was encountered at this concentration. However, complete elimination of proliferation was achieved with a dose of 10 micrograms/ml (17.8 microM), which produced a direct cytotoxic effect. We conclude that tamoxifen inhibits proliferation of cell lines derived from both low-grade and high-grade pediatric glial tumors in vitro at concentrations that may be achievable clinically with high-dose oral therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The efficacy of tamoxifen as an antiproliferative agent in vitro for benign and malignant pediatric glial tumors. 757 61

The incidence of seizures related to primary brain tumors is 20-80%. High-dose tamoxifen was recently reported as a novel treatment for patients with malignant gliomas who have failed standard therapies. Tamoxifen inhibits protein kinase C (PKC) in vitro and thus may regulate glioma cell growth by modulating intracellular signal transduction. We report a patient with a recurrent supratentorial pilocytic astrocytoma who had an untoward interaction between high-dose tamoxifen therapy and phenytoin (PHT), drugs that share a common enzyme for metabolism, therefore emphasizing the need to monitor concomitant antiepileptic drug (AED) levels when high-dose tamoxifen therapy is instituted.
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PMID:High-dose tamoxifen in treatment of brain tumors: interaction with antiepileptic drugs. 761 29

It has been shown that 17 beta-estradiol stimulates the cycle of phospholipid conversion in the breast tumor cells. The action of tamoxifen on antiestrogen cells is not limited by weakening the stimulating effect of 17 beta-estradiol on the exchange of intracellular phospholipids, but gives rise to a more complicated pattern of changes: inhibited incorporation of 32-P-phosphatidylcholine (PC) and activated exchange of phosphoinositides (PI). The experimental findings of 53 breast tumors have indicated that in 47.2% of cases Tamoxifen alters the PC/PI ratio and causes its 2-fold increase. Such alterations have been found to be induced by the ability of Tamoxifen to suppress the activity of protein kinase C that regulates the synthesis of PC and PI. It is suggested that the revealed capacity of Tamoxifen to change the rate of intracellular phospholipid conversion might be used for evaluating the efficiency of this agent on malignant tumors.
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PMID:[Evaluation of the effectiveness of tamoxifen in malignant breast tumors: new approaches]. 778 Mar 35

Tamoxifen has been shown to inhibit the proliferation of human gliomas in vitro. This inhibition is independent of tamoxifen's known anti-estrogenic properties. Tamoxifen is an inhibitor of protein kinase C (PKC), a calcium- and phospholipid-dependent serine kinase which plays a critical role in the proliferation of certain cell lines. Gliomas overexpress PCK, and their growth rate is coupled to the level of this key enzyme. As such, the effect of tamoxifen may be mediated by its inhibitory effect on PKC. To further investigate this possibility, we compared the chemosensitivity of cultured glioma lines to both tamoxifen and N-desmethyltamoxifen (DMT). DMT is the major metabolite of tamoxifen in humans and is a ten-fold more potent inhibitor of PKC. Seven lines were tested using the standard MTT assay, which quantitates metabolically active cells colorimetrically using a tetrazolium dye. Four of the seven lines were also tested using a tritiated thymidine uptake assay. In the MTT assay, all seven lines showed significantly greater sensitivity to DMT, while three of the four lines tested in the thymidine uptake assay were more sensitive to DMT. Correlation between the two assays was good. The dose of tamoxifen required to produce a 50% inhibition of optical absorbance or thymidine uptake (ID50) was typically five- to ten-fold greater than the ID50 for DMT, approximating the relative strength of the two compounds as PKC inhibitors. In addition to providing some support for the ypothesis that triphenylethylenes inhibit gliomas via PKC inhibition, these findings have clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A comparison of the relative chemosensitivity of human gliomas to tamoxifen and n-desmethyltamoxifen in vitro. 796 94

The tumor cell growth inhibitory activity of tamoxifen was enhanced significantly by verapamil treatment in an estrogen receptor positive human breast cancer cell line, MCF-7. Treatment of MCF-7 cells with 5 and 10 micrograms/mL verapamil produced a 1.8- and 2.8-fold increase, respectively, in tamoxifen activity. Unlike reversal of multi-drug resistance, the verapamil-mediated increase in tamoxifen activity was not associated with enhanced drug accumulation. Tamoxifen treatment alone or in combination with verapamil did not affect the activity of protein kinase C, an enzyme implicated in the anti-tumor activity of tamoxifen. Addition of 17 beta-estradiol in the cell survival assay system partially abrogated the modulatory effect of verapamil. These data suggest that potentiation of tamoxifen activity by verapamil may involve interaction of this agent with the estrogen receptor. In conclusion, potentiation of tamoxifen activity by calcium channel blockers represents a novel approach for improving the therapeutic results with tamoxifen in women with breast cancer.
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PMID:Potentiation of tamoxifen activity by verapamil in a human breast cancer cell line. 818 86

The in vitro effects of the epidermal growth factor (EGF) and progesterone on phospholipid turnover in cells of 19 human adenocarcinomas (postsurgical material) have been studied. In 58% of tumours EGF increased the 32P incorporation into two basic cell phospholipids--phosphatidylcholine and phosphoinositides. In EGF-insensitive cells progesterone induced no noticeable changes in the basal level of phospholipid metabolism. However, in 10 out of 11 positively responding to EGF adenocarcinomas progesterone inhibited the EGF-dependent activation of 32P incorporation into the phospholipids already on the 15th min after its addition to the cells. Analysis of effects of EGF and the anti-estrogen drug tamoxifen on phospholipid turnover in 22 human mammary tumours did not reveal any significant differences in tamoxifen effect on tumour cells differing in their sensitivity to EGF. Independently of cell sensitivity to EGF, tamoxifen caused some decrease in the 32P incorporation into phosphatidylcholine but increased the label incorporation into phosphoinositides. Tamoxifen added to tumour cells prestimulated with EGF or 17 beta-estradiol failed to abrogate the effect of these compounds on phospholipid turnover. At the same time, treatment of cells with the protein kinase C activator 12-O-tetradecanoyl-phorbol-13-acetate fully inhibited the effect of tamoxifen on phospholipid metabolism. The results obtained suggest that the EGF-dependent activation of intracellular phospholipid turnover is under the negative control of progesterone. As for tamoxifen, its effect on cells is independent of EGF and consists, apparently, in the inhibition of protein kinase C activity.
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PMID:[The effect of progesterone and tamoxifen on EGF-dependent activation of phospholipid turnover in uterine and breast tumor cells]. 836 19

Previous work has shown that PMA and diacylglycerols, activators of protein kinase C (PKC) can suppress cell polarity and locomotor activity of Walker carcinosarcoma cells in vitro, suggesting that PKC activation may result in a stop signal for tumor cell locomotion. This hypothesis was further analysed. The present results show that the DAG kinase inhibitor, R 59022, suppressed tumor cell polarity and strongly inhibited cell locomotion at a concentration of 10(-4), thus supporting the earlier finding that an increased availability of DAGs can suppress the locomotor activity of Walker carcinosarcoma cells. The results support the stop-signal hypothesis of PKC activation insofar as DAG kinase inhibition mimics the effects of DAGs and PMA. In order to clarify further the effects of protein kinase modulation on locomotion, we now extended our studies on structurally different inhibitors of protein kinases. In contrast to H-7, HA-1004 had no effect on cell polarity and did not reduce cell locomotion in the presence of colchicine, but reduced the proportion of spontaneously locomoting cells by 70% at 3 x 10(-4) M. Polymyxin B suppressed cell polarity and locomotion only at concentrations that proved to be toxic. Tamoxifen had no significant effect on cell polarity and locomotor activity. Sangivamycin did not suppress cell polarity and spontaneous locomotion at a concentration range of 10(-9) M to 10(-4) M. However, at 10(-4) M it decreased the proportion of migrating, colchicine-stimulated cells by 50%. The diverse responses to structurally different PKC inhibitors may be explained by their limited and variable specificity for PKC and different mechanisms of action on PKC.
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PMID:Shape changes and chemokinesis of Walker carcinosarcoma cells: effects of protein kinase inhibitors (HA-1004, polymyxin B, sangivamycin and tamoxifen) and an inhibitor of diacylglycerol kinase (R 59022). 839 Aug 1

Tamoxifen (TAM) markedly increases the response rate of malignant melanoma to treatment with cisplatin (DDP), carmustine, and dacarbazine, and we have previously reported that there is a highly synergistic interaction between TAM and DDP with respect to the cytotoxic effect against the human melanoma cell line T-289 (E. F. Mc Clay et al., Cancer Res., 52: 6790-6796, 1992). The mechanism underlying synergy was investigated by examining the effect of selection for either DDP or TAM resistance on the magnitude of the synergy quantitated by median effect analysis. The combination index at 50% cell kill was 0.26 +/- 0.02 (SD) for parental T-289 cells (indicating marked synergy), 0.54 +/- 0.14 for cells selected for low-level DDP resistance (indicating moderate synergy), and 1.39 +/- 0.20 for cells selected for low-level TAM resistance (indicating antagonism). Thus, factors that regulate DDP sensitivity have a moderate effect on reducing the DDP/TAM synergy, but determinants of TAM sensitivity have a major effect. The known biochemical effects of TAM include antagonism of estrogen at the estrogen receptor (ER) and inhibition of calmodulin and protein kinase C activity. T-289 cells contained undetectable amounts of ER by the dextran-coated charcoal assay and expressed only trace amounts of ER mRNA, and another more avid ER antagonist, droloxifene, failed to interact synergistically with DDP. N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a potent calmodulin antagonist, failed to demonstrate synergy with DDP, and activation of protein kinase C, instead of interacting antagonistically with DDP, yielded synergy. TAM did not alter the cell cycle phase perturbation produced by exposure to DDP alone. We conclude that the synergy between TAM and DDP is not mediated by the effects of TAM on the ER, calmodulin, protein kinase C, or cell cycle regulation. However, the factors that determine cellular sensitivity to TAM also determine whether TAM interacts synergistically with DDP.
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PMID:Tamoxifen modulation of cisplatin sensitivity in human malignant melanoma cells. 845 25


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