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

We have investigated the relationship between protein kinase C (PKC), levels of resistance and drug used for selection in a series of human KB carcinoma cell lines by comparing protein kinase C activity and PKC alpha, beta I, beta II, gamma, delta, epsilon, and zeta subspecies protein expression. PKC alpha protein expression was increased by 600% and 375% in KB-A1 and KB-C1 lines respectively over the parent KB-3-1 line; only KB-A1 cells showed increased PKC delta expression. Expression of other PKC subspecies was equal to that of KB-3-1 cells. There was considerable variation between the different KB cell lines in total cytosolic PKC activity, the KB-A1 and KB-C1 lines showing 400% and 350% increases respectively, KB-V1 and KB-8-5-11 about 180%, and KB-8-5 no increase relative to the parent KB-3-1 line. For calcium-independent PKC activity, the KB-C1 and KB-A1 lines only were increased over the KB-3-1 line. Immunoprecipitation with antisera to PKC subspecies confirmed that the increase in KB-A1 cytosolic total PKC activity was due largely to PKC alpha and partially to PKC delta. Membrane-associated PKC activity was increased by 500% and 350% in KB-A1 and KB-C1 lines respectively, by 250% and 270% in KB-V1 and KB-8-5-11, and not increased in KB-8-5 cells relative to the KB-3-1 cells. For KB-C1, KB-8-5-11, and KB-8-5 lines, which show decreasing resistance to colchicine, our results suggest a correlation between PKC and multidrug resistance in cells selected for resistance to this drug. There is no correlation between PKC and multidrug resistance for cells selected in different drugs. Our study therefore suggests that specific PKC subspecies are associated with the MDR phenotype of some KB cell lines, but that the extent of PKC involvement depends on the type of drug used for selection and its concentration.
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PMID:Changes in protein kinase C subspecies protein expression and activity in a series of multidrug-resistant human KB carcinoma cell lines. 770 29

The newly identified drug transporter MRP is functionally linked to a multiple drug resistance independent from P-glycoprotein. Resistance modifiers for this type of MDR are rare at present. We analyzed the modulating effect of the highly selective bisindolylmaleimide PKC inhibitor GF 109203X on the MRP overexpressing human MDR sublines HL60/AR and GLC4/ADR. Applying a 72 hour MTT-assay we demonstrate a complete reversal of the vincristine resistance of HL60/AR cells. Adriamycin resistance of HL60/AR, or vincristine resistance of GLC4/ADR were partially reversed. Furthermore, rhodamine 123 efflux from HL60/AR was strongly modulated by GF 109203X. Since the PKC inhibitor did not significantly influence MRP gene expression at the mRNA level which was examined by cDNA-PCR, our results suggest either a direct interaction of the compound with MRP or/and an indirect influence on MRP activity via altering the phosphorylation status of the transporter.
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PMID:The specific bisindolylmaleimide PKC-inhibitor GF 109203X efficiently modulates MRP-associated multiple drug resistance. 781 10

Acquired resistance to chemotherapeutic drugs by tumor cells is an important obstacle to effective therapy of human malignancy. These resistance cell lines originated from human or rodent have been characterized by increased expression of MDR (Multidrug-resistance) gene and P-glycoprotein which plays as efflux pump of drugs from cells. These multidrug-resistance sublines also have been reported increased activities of protein kinases and glutathione S-transferase-pi. Although there have been extensive biophysical and biochemical characterization of the differences between parental lines and MDR tumor cell sublines, morphologic observations have been limited. In this study, filamentous cytoskeletons which involve many biological phenomena such as maintenance of cell morphology, mitosis, cellular movement, transport, and adhesion, were observed by confocal laser microscopy. To compare the expression of each cytoskeletons, fluorescent intensities of cells stained for each cytoskeletons were measured by confocal laser microscopic system. Utilizing this methodology, higher microtubular expression was observed in HL-60/ADR and K562/ADR than in their parental lines, but no significant differences of actin and vimentin were observed. Phosphorylation by protein kinases has been established as a key factor in the regulation of cytoskeletal function. But little is known about the role of protein phosphorylation in cytoskeletal function. Since increased activities of PKC and PTK were detected in HL-60/ADR, the effect of PKC inhibitor, staurosporine (STR), or PTK inhibitor, genistein (GNS), on cell growth was detected. STR and GNS reduced the resistance to Adriamycin in HL-60/ADR. Furthermore, STR and GNS disrupted the filamentous structure of microtubules in HL-60/ADR, and suppressed the expression of microtubules to 37%, and 49%, respectively. In contrast, PKC activator, phorbol ester (TPA), caused stronger microtubular assembling in HL-60/ADR, and increased the expression of microtubules to 134%. Resulting from this study, it is likely that acquired MDR of HL-60 and K562 was associated with increased expression of microtubules, and microtubular assembling or disassembling was considered to be regulated in part by PKC and PTK.
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PMID:[Features of filamentous cytoskeletons in acquired multidrug-resistance of HL-60 human leukemia cell line]. 790 88

The phospholipase D (PLD)-mediated synthesis of phosphatidylethanol (PtdEtOH) and the hydrolysis of phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho) were examined in drug-sensitive and multidrug-resistant lines of MCF-7 human breast carcinoma cells. In drug-sensitive (MCF-7/WT) cells, the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) failed to enhance either the synthesis of PtdEtOH or the hydrolysis of either phospholipid. In the drug-resistant (MCF-7/MDR) cells, 100 nM PMA greatly enhanced both the synthesis of PtdEtOH (approximately 21-fold) and the hydrolysis of PtdEtn (approximately 29-fold), but had no effect on the hydrolysis of PtdCho. The PLD activators sphingosine and H2O2 were found to elicit only a slight (1.28-1.4-fold) stimulatory effect on PtdCho hydrolysis in both the MCF-7/WT and MCF-7/MDR cell types, and had only a small effect on PtdEtn hydrolysis in the MCF-7/WT cells as well. However, these agents significantly (approximately 2.6-3.5-fold) stimulated PtdEtn hydrolysis in the MCF-7/MDR cells. These data indicate that MCF-7/MDR cells contain a PtdEtn-specific PLD activity which can be selectively stimulated by PMA, sphingosine and H2O2.
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PMID:Phorbol ester selectively stimulates the phospholipase D-mediated hydrolysis of phosphatidylethanolamine in multidrug-resistant MCF-7 human breast carcinoma cells. 794 88

KB-A1 and KB-A10 are 2 multi-drug-resistant cell lines which are 100- and 1,000-fold resistant to Adriamycin, respectively. We have examined the expression of P-glycoprotein at the molecular and cellular levels in these human carcinoma cells. Both MDR cell lines, when compared to the parental KB-3-1, show characteristic increases in mdr 1 gene copy number, an increase in mdr 1 mRNA expression, a corresponding increase in transcription rate and a consequent over-expression of P-glycoprotein. However, the more highly resistant KB-A10 cells have a lower gene copy number, express less mdr 1 mRNA and contain less P-glycoprotein than the A1 cell line. To determine whether higher levels of cellular resistance were attributable to enhanced efficacy of P-glycoprotein or to other cellular regulatory mechanisms, we examined other major cellular properties known to be associated with the mdr phenotype. Both the KB-A1 and KB-A10 lines exhibit similar increases in protein kinase C activity as compared to the drug-sensitive parent. In addition, neither glutathione-S-transferase nor topoisomerase II activities account for enhanced resistance of the KB-A10 cells. The above observations are contrary to the premise that the level of drug resistance is necessarily proportional to expression of P-glycoprotein or to other common factors thought to participate in drug insensitivity; consequently, new mechanisms of resistance must be in operation in these cells.
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PMID:Anomalous expression of P-glycoprotein in highly drug-resistant human KB cells. 809 16

Resistance of tumor cells to doxorubicin is a multifactorial phenomenon. In the present investigation, the ability of resistance modifiers against different resistance mechanisms was analysed. Substances which block P-glycoprotein (P-170) function circumvented resistance of doxorubicin-resistant sarcoma 180 (S180) cells completely (verapamil, thioridazine) or partially (hycanthone), whereas inhibitors of glutathione S-transferase (ethacrynic acid, N-ethylmaleimide, buthionine sulfoximine), and protein kinase C (staurosporine, acridine orange) caused only a partial reversion of resistance. In contrast, an inhibitor of alkaline phosphatase (levamisole) did not overcome doxorubicin-resistance. These results indicate that P-glycoprotein blockers might be more effective to modulate doxorubicin-resistance of S180 cells as compared to other modifiers. Further investigations using other MDR cell lines are required to clarify the generality of these findings.
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PMID:Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms. 810 93

The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance (P-gp-MDR) is a decrease of steady state drug levels as compared to drug-sensitive controls. Recently it has been pointed out that there appears to be a discrepancy between the amount of drug accumulated at steady state by drug-sensitive and highly resistant cells and their degree of resistance. These observations could suggest two things: (1) that factors other than drug accumulation may be important in MDR, (2) that they reflect a discrepancy between the short-term measurements of drug accumulation at 60 min versus long-term (72 hr) growth inhibition. Due to the different experimental conditions and the different type of cells used it is very difficult to compare the literature data. For this reason we have investigated the effect of 12 compounds in overcoming resistance in relation to drug accumulation. We have used a spectrofluorometric method which allows the determination of the nuclear drug accumulation directly on living cells. Our data clearly establish that, at least for the compounds used in that study, there is a very good correlation between their ability to increase drug accumulation, measured at short-term, and their ability to reverse MDR accumulation, measured at short-term, and their ability to reverse MDR, but no correlation with their ability to inhibit protein kinase C activity. In addition, their efficiency to reverse MDR correlates with their pKa values, the efficiency being the highest when the pKa is the lowest.
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PMID:Correlation between the short-term measurements of drug accumulation in living cells and the long-term growth inhibition. 820 2

The bladder carcinoma cell line J82-NVB was selected for resistance to the new vinca alkaloid Navelbine. These cells possessed a non-MDR phenotype and were cross-resistant to vinca alkaloids and taxoids. Some morphological differences between sensitive (J82) and resistant (J82-NVB) cells were observed J82 cells had a heterogeneous population morphology with both epithelial and spindle shaped cells, while J82-NVB cells were almost all of the epithelial type. Vimentin intermediate filaments were less organized in J82-NVB than in J82 cells. Moreover, desmosomes were present in the membranes of J82NVB cells but not in J82 cells. These findings suggest that J82 cells are poorly differentiated epithelial cells while J82-NVB cells possess some characteristics of a more differentiated epithelial cell line. After a two-week treatment with all-trans retinoic acid, all the cells became spindle shaped, vimentin filaments reappeared in the cytoplasm of J82-NVB cells and desmosomes disappeared from the membranes of these cells. These changes were accompanied by a decrease from 17 to 4.6 of the resistance factor of J82-NVB cells to Navelbine. This decrease in resistance was concomitant with modifications of microtubules assembly regulation mechanisms. After Navelbine treatment, microtubule reassembly occurred in resistant but not in sensitive nor in retinoic acid treated cells. Okadaic acid, a protein phosphatase inhibitor, inhibited microtubule reassembly in resistant cells, and 2-aminopurine, a protein kinase inhibitor, induced microtubule reassembly in sensitive cells after Navelbine treatment. These findings show that microtubule reassembly after depolymerization is regulated by the kinase/phosphatase systems. A treatment with phorbol myristate acetate (PMA), a protein kinase C (PKC) agonist, induced the same morphological modifications and resistance decrease as retinoic acid treatment. A specific PKC inhibitor (Bisindolymaleimide) prevented these PMA-induced morphological modifications and resistance decrease in J82-NVB cells, showing that these effects were mediated by PKC. This study suggests that, in part by acting on some properties of the cytoskeleton, the differentiation modulator, retinoic acid, and the signal transduction modulator, phorbol myristate acetate, can decrease the resistance of J82-NVB cells to microtubule poisons.
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PMID:Concomitant decrease of resistance and modifications of the cytoskeleton after all-trans retinoic acid and phorbol ester treatments in a navelbine-resistant bladder carcinoma cell line. 913 63

We recently demonstrated a correlation between the expression levels of the PKC eta isozyme and the MDR1 or MRP genes in blasts from AML patients, and in primary breast cancers. In order to extend these findings we analysed ovarian cancer cells from 14 ascites aspirates from 8 patients using a cDNA-PCR approach. 5 patients were examined in follow up studies. 4 out of these 5 patients received continuous chemotherapy. The relative increases in MDR1, MRP, LRP or PKC eta mRNA expression levels were monitored. In one of these patients combined significant increase in MDR1, MRP, LRP and PKC was seen. One follow up sample was obtained after chemotherapy was discontinued. In this case significant relative decreases of MDR1, LRP and PKC eta mRNA expression levels were found. Furthermore, a significant positive correlation was determined for the relative mRNA expression levels of MRP and PKC eta. These results point to a multifactorial emergence of MDR in this type of tumor with a possible involvement of the PKC eta isozyme.
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PMID:Expression analysis of protein kinase C isozymes and multidrug resistance associated genes in ovarian cancer cells. 961 8

Drug resistance, especially in its multiple forms (multidrug resistance, MDR), is a major and difficult problem to resolve in cancer therapy. Certain cytokines might be capable of bypassing this process and here we report on the in vitro effects of Tumor Necrosis Factor alpha, (TNF) on a MDR variant (FLC/DOX) of Friend leukemia. Drug resistance of FLC/DOX is associated with at least two mechanisms, i.e. overexpression of P-glycoprotein and increase in glutathione-related detoxifying activities. Nevertheless, TNF exerts more cytotoxicity in FLC/DOX than in its parental, drug-sensitive, counterpart and this effect is related to the induction of apoptosis. In contrast, Doxorubicin (DOX) never induces apoptosis in FLC/DOX, even when applied at high, fully cytotoxic, concentrations. We have tried to elucidate TNF signaling in FLC/DOX. The results have indicated that in this cell line TNF-triggered apoptosis exhibits some distinct features. It occurs mostly through type I (p55) TNF receptors, probably involves a calphostin-C sensitive protein kinase C activity and requires synthesis of proteins (it is inhibited by actinomycin D or cycloheximide) and of inducible nitric oxide (NO) synthase (it is inhibited by NG-methyl-L-arginine or aminoguanidine). Further, it is not influenced by agents which increase or decrease cell sulfhydryl groups, such as N-acetylcysteine or buthionine sulfoximine, respectively. These steps appeared to be either not or dissimilarly involved in the resistance to DOX of the same cells. In particular, DOX activity was stimulated by calphostin C and buthionine sulfoximine, and reduced by N-acetyl-cysteine. These findings illustrate that TNF may activate fresh cytotoxic pathways in tumor cells which are multidrug resistant, also owing to multifactorial causes.
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PMID:The apoptotic signaling of TNF-alpha in multidrug resistant Friend leukemia cells. 971 11


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