Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the epidermal growth factor receptor family member HER2 is found in approximately 30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu-driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier.
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PMID:Trastuzumab-resistant HER2-driven breast cancer cells are sensitive to epigallocatechin-3 gallate. 1790 3

MDA-MB-435S human breast cancer cells (435S) secrete nucleoside diphosphate kinase (NDPK) that supports metastases and is inhibited by epigallocatechin gallate (EGCG) and ellagic acid (EA). We hypothesise that 435S cell-secreted NDPK-B supports tumour formation by modulating ATP levels locally to activate endothelial cell (EC) P2Y receptor-mediated angiogenesis. Epigallocatechin gallate (IC50=8-10 microM) and EA (IC50=2-3 microM) suppressed 435S cell growth, but had less effect on human CD31+ EC growth. Epigallocatechin gallate (IC50=11 microM) and EA (IC50=1 microM) also prevented CD31+ EC tubulogenesis on Matrigeltrade mark. 435S cell-conditioned media induced tubulogenesis in a cell number, time, and nucleotide-dependent manner. Ellagic acid (1 microM), but not equimolar EGCG, reduced cell number-dependent angiogenesis. P2Y 1 receptor activation by NDPK-generated nucleotide (100 microM ATP) or by 10 microM 2-methyl-thio-ATP (2MS-ATP) promoted tubulogenesis on collagen and was blocked by the P2Y 1 antagonist MRS2179 (10 microM). Physiological amounts of purified as well as 435S cell-secreted NDPK also promoted angiogenesis that was attenuated by NDPK depletion or 10 microM MRS2179, indicating a P2Y 1 receptor-mediated pathway. These results support the notion that secreted NDPK mediates angiogenesis via P2Y receptor signalling and suggests that novel inhibitors of NDPK may be useful as therapeutics.
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PMID:Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase. 1794 May 13

The V-ATPases are ATP-dependent proton pumps, found in virtually all cells, responsible for acidification of organelles and energizing of plasma membranes. Its role in diseases, such as osteoporosis and metastatic cancer, makes the V-ATPase a potential drug target. Short synthetic peptides that are presented here mimic the 7th transmembrane domain (TM7) of subunit a (Vph1p) of Saccharomyces cerevisiae V-ATPase, an essential part of the membrane-bound VO domain, where proton translocation takes place. The peptides adopt a transmembrane configuration only in membranes containing anionic lipids, stressing the importance of strong interfacial anchoring by the flanking lysines. Peptide P1, which contains the essential arginine R735, is monomeric, whereas peptide P2, which lacks this extra charge, tends to aggregate in the membrane. SB 242784, which is a highly potent inhibitor of V-ATPase, does not show any interaction with the peptides, indicating that TM7 alone is not sufficient for inhibitor binding.
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PMID:Membrane-bound peptides from V-ATPase subunit a do not interact with an indole-type inhibitor. 1806 32

The aquaporins (AQPs) are small, integral-membrane proteins that selectively transport water across cell plasma membranes. A subset of AQPs, the aquaglyceroporins, also transport glycerol. AQPs are strongly expressed in tumor cells of different origins, particularly aggressive tumors. Recent discoveries of AQP involvement in cell migration and proliferation suggest that AQPs play key roles in tumor biology. AQP1 is ubiquitously expressed in tumor vascular endothelium, and AQP1-null mice show defective tumor angiogenesis resulting from impaired endothelial cell migration. AQP-expressing cancer cells show enhanced migration in vitro and greater local tumor invasion, tumor cell extravasation, and metastases in vivo. AQP-dependent cell migration may involve AQP-facilitated water influx into lamellipodia at the front edge of migrating cells. The aquaglyceroporin AQP3, which is found in normal epidermis and becomes upregulated in basal cell carcinoma, facilitates cell proliferation in different cell types. Remarkably, AQP3-null mice are resistant to skin tumorigenesis by a mechanism that may involve reduced tumor cell glycerol metabolism and ATP generation. Together, the data suggest that AQP expression in tumor cells and tumor vessels facilitates tumor growth and spread, suggesting AQP inhibition as a novel antitumor therapy.
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PMID:Aquaporins--new players in cancer biology. 1831 71

Renal medullary carcinoma is a rare, well-recognized highly aggressive tumor of varied histopathology, which occurs in young patients with sickle cell trait or disease. Rhabdoid elements, occasionally seen in high-grade renal tumors including renal medullary carcinoma, possibly represent a pathologic marker of aggressive behavior. INI1 (hSNF5/SMARCB1/BAF47) is a highly conserved factor in the ATP-dependent chromatin-modifying complex. Loss of this factor in mice results in aggressive rhabdoid tumors or lymphomas. In humans, the loss of INI1 expression has been reported in pediatric renal rhabdoid tumors, central nervous system atypical teratoid/rhabdoid tumors and epithelioid sarcomas, a possible primary soft tissue rhabdoid tumor. This study compares five renal medullary carcinomas with 10 high-grade renal cell carcinomas (five with rhabdoid features), two urothelial carcinomas and two pediatric renal rhabdoid tumors. All five renal medullary carcinomas, irrespective of histopathology, showed complete loss of INI1 expression similar to that seen in pediatric renal rhabdoid tumors. In contrast, all renal cell carcinomas or urothelial carcinomas, including those with histological rhabdoid features, expressed INI1. Clinically, all five of the patients with renal medullary carcinoma and the two patients with rhabdoid tumors presented with extra-renal metastases at the time of diagnosis. This study demonstrates that renal medullary carcinoma and renal rhabdoid tumor share a common molecular/genetic alteration, which is closely linked to their aggressive biological behavior. However, the absence of INI1 expression is not necessarily predictive of rhabdoid histopathology but remains associated with aggressive behavior in renal medullary carcinoma.
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PMID:Renal medullary carcinoma: rhabdoid features and the absence of INI1 expression as markers of aggressive behavior. 1832 9

Our aim was to study the possible alterations of redox status (enzymatic and nonenzymatic parameters and metal elements) in erythrocytes of patients with hepatocellular carcinoma (HCC), colorectal liver metastases (CRLM) and benign liver neoplasms. The function of redox homeostasis is closely connected to the energy level of erythrocytes, therefore, the ATP level was also determined. Antioxidant parameters, enzyme activities of superoxide dismutase and glutathione peroxidase were estimated in the erythrocytes of 11 patients with benign tumour, 23 patients with primary malignant and 37 metastatic liver tumour patients and 30 age-matched and sex-matched healthy controls. Element content with inductively coupled plasma optical emission spectrometer and ATP level by the chemiluminometric method were also determined from the samples. Free radical intensity was significantly increased, whereas erythrocyte glutathione peroxidase and superoxide dismutase activities were significantly decreased in the HCC and CRLM groups versus benign groups and controls. Se, Mn and Zn levels were lowered in HCC and CRLM groups versus benign and control groups. The content of Cu, Mg, Se and Zn changed significantly between HCC and CRLM groups. Similarly, ATP concentration decreased in HCC and CRLM versus controls and benign groups. The lowest levels of ATP and antioxidant enzyme activities were found in the case of CRLM patients. These results reveal an alteration in the ATP level of erythrocytes with concomitant changes in the antioxidant defence system in hepatic cancer patients. Altered redox homeostasis (oxidative damage) may lead to decreased ATP level and consequently may play an important role in primary carcinogenesis and generation of metastases, as well.
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PMID:Oxidative stress with altered element content and decreased ATP level of erythrocytes in hepatocellular carcinoma and colorectal liver metastases. 1840 40

Most GIST patients develop clinical resistance to KIT/PDGFRA tyrosine kinase inhibitors (TKI). However, it is unclear whether clinical resistance results from single or multiple molecular mechanisms in each patient. KIT and PDGFRA mutations were evaluated in 53 GIST metastases obtained from 14 patients who underwent surgical debulking after progression on imatinib or sunitinib. To interrogate possible resistance mechanisms across a broad biological spectrum of GISTs, inter- and intra-lesional heterogeneity of molecular drug-resistance mechanisms were evaluated in the following: conventional KIT (CD117)-positive GISTs with KIT mutations in exon 9, 11 or 13; KIT-negative GISTs; GISTs with unusual morphology; and KIT/PDGFRA wild-type GISTs. Genomic KIT and PDGFRA mutations were characterized systematically, using complementary techniques including D-HPLC for KIT exons 9, 11-18 and PDGFRA exons 12, 14, 18, and mutation-specific PCR (V654A, D820G, N822K, Y823D). Primary KIT oncogenic mutations were found in 11/14 patients (79%). Of these, 9/11 (83%), had secondary drug-resistant KIT mutations, including six (67%) with two to five different secondary mutations in separate metastases, and three (34%) with two secondary KIT mutations in the same metastasis. The secondary mutations clustered in the KIT ATP binding pocket and kinase catalytic regions. FISH analyses revealed KIT amplicons in 2/10 metastases lacking secondary KIT mutations. This study demonstrates extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST. KIT kinase resistance mutations were not found in KIT/PDGFRA wild-type GISTs or in KIT-mutant GISTs showing unusual morphology and/or loss of KIT expression by IHC, indicating that resistance mechanisms are fundamentally different in these tumours. Our observations underscore the heterogeneity of clinical TKI resistance, and highlight the therapeutic challenges involved in salvaging patients after clinical progression on TKI monotherapies.
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PMID:Heterogeneity of kinase inhibitor resistance mechanisms in GIST. 1862 23

Metabonomic profiling using proton nuclear magnetic resonance ((1)H NMR) spectroscopy and multivariate data analysis of human serum samples was used to characterize metabolic profiles in renal cell carcinoma (RCC). We found distinct, easily detectable differences between (a) RCC patients and healthy humans, (b) RCC patients with metastases and without metastases, and (c) RCC patients before and after nephrectomy. Compared to healthy human serum, RCC serum had higher levels of lipid (mainly very low-density lipoproteins), isoleucine, leucine, lactate, alanine, N-acetylglycoproteins, pyruvate, glycerol, and unsaturated lipid, together with lower levels of acetoacetate, glutamine, phosphatidylcholine/choline, trimethylamine-N-oxide, and glucose. This pattern was somewhat reversed after nephrectomy. Altered metabolite concentrations are most likely the result of the cells switching to glycolysis to maintain energy homeostasis following the loss of ATP caused by impaired TCA cycle in RCC. Serum NMR spectra combined with principal component analysis techniques offer an efficient, convenient way of depicting tumour biochemistry and stratifying tumours under different pathophysiological conditions. It may be able to assist early diagnosis and postoperative surveillance of human malignant diseases using single blood samples.
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PMID:Metabonomic profiling of renal cell carcinoma: high-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis. 1870 33

Most of the effects described for bisphosphonates (pC(R1)(R2)p) are related, directly or indirectly with a pyrophosphate moiety. Bisphosphonates are (i) analogs of pyrophosphate in the synthesis of ATP derivatives (AppC(R1)(R2)p) catalyzed by ligases and (ii) inhibitors of enzymes of the mevalonate pathway with substrates containing a terminal pyrophosphate. Searching for the role of bisphosphonates on other reactions involving pyrophosphate, we explored their effect on a phosphoribosyltransferase activity, present in Saccharomyces cerevisiae cell extracts, using 5-fluorouracil or uracil as substrates. Unexpectedly, bisphosphonates increased the initial rate of synthesis of 5-FUMP (from 5-fluorouracil and phosphoribosylpyrophosphate): etidronate (2.8+/-0.3 times); pamidronate (2.6+/-0.4 times); alendronate (2.5+/-0.6 times) and clodronate (2.0+/-0.1 times). Similar values for the synthesis of UMP (from uracil and phosphoribosylpyrophosphate) were obtained in the presence of bisphosphonates. The values of the activation constants determined for alendronate and clodronate for the synthesis of UMP were 0.05+/-0.02 mM and 0.32+/-0.22 mM, respectively. These results raise the possibility that bisphosphonates enhance the effect of 5-fluorouracil (or other uracil prodrugs) in the treatment of bone tumors or bone tumor metastases.
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PMID:Bisphosphonates activate the 5-fluorouracil/uracil phosphoribosyltransferase activity present in Saccharomyces cerevisiae cell extracts: implications for tumor treatments. 1870 99

The adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is a chemosensitivity test that offers the potential of selecting cancer treatments based on the responsiveness of individual tumors. We report a case of 47-yr-old male, presented with sigmoid colon cancer with multiple liver and peritoneal metastases, in which there was a complete response for the primary colon cancer after administration of preoperative chemotherapy selected by ATP-CRA. Oxaliplatin was the most sensitive drug based on the ATP-CRA where the specimen obtained by ultrasound- guided percutaneous liver biopsy was used. After twelve cycles of oxaliplatincapecitabine chemotherapy, abdominopelvic computed tomography revealed marked shrinkage of the liver metastases and positron emission tomography showed no uptake of 18F-fluoro-deoxy-glucose (FDG) either in the liver or peritoneum except localized uptake in the sigmoid colon. The patient underwent an anterior resection and radiofrequency ablation of the liver metastases, which resulted in a macroscopic curative resection of the cancer cells. Histological examination revealed no residual cancer cells in the resected specimen of the sigmoid colon. This result suggested that preoperative chemotherapy chosen by ATP-CRA may be useful for treating advanced colon cancer with unresectable liver and peritoneal metastases.
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PMID:Complete remission of unresectable colon cancer after preoperative chemotherapy selected by adenosine triphosphate-based chemotherapy response assay. 1895 6


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