Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin is a key drug in chemotherapy for lung cancer. It has been reported that intracellular accumulation of cisplatin is an important step as a determinant for resistance to cisplatin, which may be modulated by Na+, K+-ATPase activity. And it has been reported that isoproterenol, a beta-adrenoceptor agonist, enhances sensitivity to cisplatin in non-small cell lung cancer (NSCLC) cell lines. In this study, the effects of the selective beta1, beta2, and beta3-adrenoceptor agonists on membrane Na+, K+-ATPase activity and sensitivity to cisplatin were evaluated using human non-small cell lung cancer cell line. In the NSCLC cell line, sensitivity to cisplatin was improved by treatment with procaterol, a selective beta2-adrenoceptor agonist. Na+, K+-ATPase was activated and intracellular accumulation of cisplatin increased with the treatment. However, beta1 or beta3-adrenoceptor agonist did not modulate sensitivity to cisplatin or Na+, K+-ATPase activity. These results suggest that beta2-adrenoceptor may be one of the determinants for sensitivity to cisplatin in NSCLC. Exogenous beta2-adrenoceptor agonists may improve the antitumor effect of chemotherapy involving cisplatin.
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PMID:Selective beta2-adrenoceptor agonist enhances sensitivity to cisplatin in non-small cell lung cancer cell line. 1060 90

Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs may overcome the intrinsic and / or acquired resistance of cancer cells to DDP, we investigated the effect of a combination of DDP with paclitaxel and a combination of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsically resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations showed additive to synergistic antitumor activity. A time-dependent platinum (Pt) accumulation was observed in the DDP-sensitive KF cell line, while a decrease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines by exposure to paclitaxel or SN-38. Ouabain, a Na(+),K(+)-ATPase inhibitor, decreased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxel- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP), which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DDP alone. These results suggest that paclitaxel and SN-38 overcome DDP resistance of ovarian cell lines by controlling intracellular accumulation of DDP via both the influx and efflux systems.
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PMID:Paclitaxel and SN-38 overcome cisplatin resistance of ovarian cancer cell lines by down-regulating the influx and efflux system of cisplatin. 1171 50

Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorly-differentiated ovarian carcinomas treated with cisplatin-based chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy.
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PMID:Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP. 1221 79

Initiation of apoptosis by many agents is preceded by mitochondrial dysfunction and depolarization of the mitochondrial inner membrane. Here we demonstrate that, in renal proximal tubular cells (RPTC), cisplatin induces mitochondrial dysfunction associated with hyperpolarization of the mitochondrial membrane and that these events are mediated by protein kinase C (PKC)-alpha and ERK1/2. Cisplatin induced sustained decreases in RPTC respiration, oxidative phosphorylation, and increases in the mitochondrial transmembrane potential (deltaPsi(m)), which were preceded by the inhibition of F(0)F(1)-ATPase and cytochrome c release from the mitochondria, accompanied by caspase-3 activation, and followed by RPTC apoptosis. Cisplatin also decreased active Na+ transport as a result, in part, of the inhibition of Na+/K(+)-ATPase. These changes were preceded by PKC-alpha and ERK1/2 activation. Inhibition of cisplatin-induced PKC-alpha and ERK1/2 activation using Go6976 and PD98059, respectively, abolished increases in deltaPsi(m), diminished decreases in oxidative phosphorylation, active Na+ transport, and decreased caspase-3 activation without blocking cytochrome c release. Caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) did not prevent increases in deltaPsi(m). Furthermore, inhibition of PKC-alpha did not prevent cisplatin-induced ERK1/2 activation. We concluded that in RPTC: 1) cisplatin-induced mitochondrial dysfunction, decreases in active Na+ transport, and apoptosis are mediated by PKC-alpha and ERK1/2; 2) PKC-alpha and ERK1/2 mediate activation of caspase-3 by acting downstream of cytochrome c release from mitochondria; and 3) ERK1/2 activation by cisplatin occurs through a PKC-alpha-independent pathway.
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PMID:Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells. 1221 54

Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na(+), K(+)-ATPase and Ca(2+)-ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na(+), K(+)-ATPase and Ca(2+)-ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property.
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PMID:D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs. 1662 67

In ovarian cancer treatment, the chemotherapy drug cisplatin often induce drug resistance after prolonged use, causing cancer relapse and the eventual deaths of patients. Cisplatin-induced drug resistance is known to involve a complex set of cellular changes but its molecular mechanism(s) remain unclear. In this study, we designed a systems biology approach to examine global protein level and network level changes by comparing Proteomics profiles between cisplatin-resistant cell lines and cisplatin-sensitive cell lines. First, we used an experimental proteomics method based on a Label-free Liquid Chromatography / Mass Spectrometry (LC/MS) platform to obtain a list of 119 proteins that are differentially expressed in the samples. Second, we expanded these proteins into a cisplatin-resistant activated sub-network, which consists of 1230 proteins in 1111 protein interactions. An examination of network topology features reveals the activated responses in the network are closely coupled. Third, we examined sub-network proteins using Gene Ontology categories. We found significant enrichment of proton-transporting ATPase and ATP synthase complexes in addition to protein binding proteins. Fourth, we examined sub-network protein interaction function categories using 2-dimensional visualization matrixes. We found that significant cellular physiological responses arise from endogenous, abiotic, and stress-related signals, which correlates well with known facts that internalized cisplatin cause DNA damage and induce cell stress. Fifth and finally, we developed a new visual representation structure for display of activated sub-networks using functional categories as network nodes and their crosstalk as network edges. This type of sub-network further shows that while cell communication and cell growth are generally important to tumor mechanisms, molecular regulation of cell differentiation and development caused by responses to genomic-wide stress seem to be more relevant to the acquisition of drug resistance.
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PMID:A systems biology case study of ovarian cancer drug resistance. 1736 59

Cisplatin-induced drug resistance is known to involve a complex set of cellular changes whose molecular mechanism details remain unclear. In this study, we developed a systems biology approach to examine proteomics- and network-level changes between cisplatin-resistant and cisplatin-sensitive cell lines. This approach involves experimental investigation of differential proteomics profiles and computational study of activated enriched proteins, protein interactions, and protein interaction networks. Our experimental platform is based on a Label-free liquid Chromatography/mass spectrometry proteomics platform. Our computational methods start with an initial list of 119 differentially expressed proteins. We expanded these proteins into a cisplatin-resistant activated sub-network using a database of human protein-protein interactions. An examination of network topology features revealed the activated responses in the network are closely coupled. By examining sub-network proteins using gene ontology categories, we found significant enrichment of proton-transporting ATPase and ATP synthase complexes activities in cisplatin-resistant cells in the form of cooperative down-regulations. Using two-dimensional visualization matrixes, we further found significant cascading of endogenous, abiotic, and stress-related signals. Using a visual representation of activated protein categorical sub-networks, we showed that molecular regulation of cell differentiation and development caused by responses to proteome-wide stress as a key signature to the acquired drug resistance.
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PMID:A systems biology approach to the study of cisplatin drug resistance in ovarian cancers. 1758 67

ATP7B is a P-type ATPase that mediates the efflux of copper. Recent studies have demonstrated that ATP7B regulates the cellular efflux of cisplatin (DDP) and controls sensitivity to the cytotoxic effects of this drug. To determine whether DDP is a substrate for ATP7B, DDP transport was assayed in vesicles isolated from Sf9 cells infected with a baculovirus that expressed either the wild-type ATP7B or a mutant ATP7B that was unable to transport copper as a result of conversion of the transmembrane metal binding CPC motif to CPA. Only the wild-type ATP7B-expressing vesicles exhibited copper-dependent ATPase activity, copper-induced acyl-phosphate formation, and ATP-dependent transport of copper. The amount of DDP that became bound was higher for vesicles expressing either type of ATP7B than for those not expressing either form of ATP7B, but only the vesicles expressing wild-type ATP7B mediated ATP-dependent accumulation of the drug. At pH 4.6, the vesicles expressing the wild-type ATP7B exhibited ATP-dependent accumulation of DDP with an apparent K(m) of 1.2 +/- 0.5 (S.E.M.) muM and V(max) of 0.03 +/- 0.002 (S.E.M.) nmol/mg of protein/min. DDP also induced the acyl-phosphorylation of ATP7B but at a much slower rate than copper. Copper and DDP each inhibited the ATP-dependent transport of the other. These results establish that DDP is a substrate for ATP7B but is transported at a much slower rate than copper.
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PMID:Transport of cisplatin by the copper efflux transporter ATP7B. 1797 67

Cisplatin is a widely used chemotherapeutic agent for treatment of ovarian, testicular, lung, and stomach cancers. The initial response to the drug is robust; however, tumor cells commonly develop resistance to cisplatin, which complicates treatment. Recently, overexpression of the Cu-ATPase ATP7B in ovary cells was linked to the increased cellular resistance to cisplatin; and the role for Cu-ATPases in the export of cisplatin from cells was proposed. Our results support functional interactions between cisplatin and ATP7B but argue against the active transport through the copper translocation pathway as a mechanism of drug resistance. In hepatocytes, we observed no correlation between the levels of endogenous ATP7B and the resistance of cells to cisplatin. Unlike copper, cisplatin does not induce trafficking of ATP7B in hepatoma cells, neither does it compete with copper in a transport assay. However, cisplatin binds to ATP7B and stimulates catalytic phosphorylation with EC(50) similar to that of copper. Mutations of the first five N-terminal copper-binding sites of ATP7B do not inhibit the cisplatin-induced phosphorylation of ATP7B. In contrast, the deletion of the first four copper-binding sites abolishes the effect of cisplatin on the ATP7B activity. Thus, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug. The link between changes in copper homeostasis and cisplatin resistance was confirmed by treating the Huh7 cells with copper chelator and increasing their resistance to cisplatin.cisplatin.
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PMID:Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug. 1914 20

Cisplatin is a platinum-containing antitumour agent, the usefulness of which is limited by nephrotoxicity. In the present study, we examined the effects of cisplatin on the established renal epithelial A6 cell line, which forms a polarized monolayer in vitro with active transmembrane ion transport. The effect of cisplatin (0-800 mum) on transepithelial ion transport and transepithelial resistance (TER) was monitored by the short-circuit current (SSC) technique. Cell integrity was determined by monitoring TER at increasing concentration of cisplatin during 24 hours. The half-maximal inhibition concentration was 49 and 540 mum when applied to either the basolateral or apical surface, respectively. This suggests that cisplatin-mediated deterioration of cell integrity is far more pronounced when cisplatin is applied basolaterally than apically. Continuous measurements of TER demonstrated a dose- and time-dependent decline in TER/TER(0) (TER at time zero). In addition, cisplatin from the basolateral side had no prompt effect on transepithelial ion transport. Instead a slow, but dose-dependent decline which at the highest concentration resembled the decline observed when ouabain was added. Inhibition of Na-K-ATPase by cisplatin was examined by the use of nystatin, a membrane permeabilizer, and data suggest that cisplatin at 800 mum inhibits Na-K-ATPase by about 50% after 60 minutes of exposure. Morphological examinations of subcultured cisplatin treated cells indicate that cell death is probably due to apoptosis rather than necrosis.
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PMID:Effect of Cisplatin on transepithelial resistance and ion transport in the a6 renal epithelial cell line. 2065 24


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