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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The impact of STS was evaluated by measuring the onset of growth of LX-1 human small cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was a decrease in the time to tumor progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.
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PMID:Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. 1065 63

The proteomic definition of plasma membrane proteins is an important initial step in searching for novel tumor marker proteins expressed during the different stages of cancer progression. However, due to the charge heterogeneity and poor solubility of membrane-associated proteins this subsection of the cell's proteome is often refractory to two-dimensional electrophoresis (2-DE), the current paradigm technology for studying protein expression profiles. Here, we describe a non-2-DE method for identifying membrane proteins. Proteins from an enriched membrane preparation of the human colorectal carcinoma cell line LIM1215 were initially fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE, 4-20%). The unstained gel was cut into 16 x 3 mm slices, and peptide mixtures resulting from in-gel tryptic digestion of each slice were individually subjected to capillary-column reversed phase-high performance liquid chromatography (RP-HPLC) coupled with electrospray ionization-ion trap-mass spectrometry (ESI-IT-MS). Interrogation of genomic databases with the resulting collision-induced dissociation (CID) generated peptide ion fragment data was used to identify the proteins in each gel slice. Over 284 proteins (including 92 membrane proteins) were identified, including many integral membrane proteins not previously identified by 2-DE, many proteins seen at the genomic level only, as well as several proteins identified by expressed sequence tags (ESTs) only. Additionally, a number of peptides, identified by de novo MS sequence analysis, have not been described in the databases. Further, a "targeted" ion approach was used to unambiguously identify known low-abundance plasma membrane proteins, using the membrane-associated A33 antigen, a gastrointestinal-specific epithelial cell protein, as an example. Following localization of the A33 antigen in the gel by immunoblotting, ions corresponding to the theoretical A33 antigen tryptic peptide masses were selected using an "inclusion" mass list for automated sequence analysis. Six peptides corresponding to the A33 antigen, present at levels well below those accessible using the standard automated "nontargeted" approach, were identified. The membrane protein database may be accessed via the World Wide Web (WWW) at http://www.ludwig. edu.au/jpsl/jpslhome.html.
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PMID:Proteomic analysis of the human colon carcinoma cell line (LIM 1215): development of a membrane protein database. 1087 Sep 58

The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. beta-Catenin-Tcf (BCT)-dependent Wnt signaling is influenced by the short-chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT-dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT-116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild-type HCT-116 cells having mutant beta-catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin D1 promoters, whereas in HCT-116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex-DNA binding. Butyrate reduces the expression of Tcf4 in HCT-116 cells, consistent with the induction by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate.
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PMID:Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate. 1177 42

Hemophilia is a rare congenital bleeding disorder that is due to the deficiency of blood coagulation factor VIII or IX. Recurrent musculoskeletal bleeding is common and bleeding into joints results in a chronic inflammatory condition termed hemophilic synovitis. This destructive process is characterized by hemosiderin deposition in the superficial and deeper layers of the synovial membrane as well as a proliferation of synovial fibroblasts and vascular cells. The hyperplastic synovium and neovascular changes are reminiscent of the histopathologic appearance observed in malignant tissues. Indeed, the benign hyperplastic synovium in patients with hemophilia displays similar invasive and destructive behaviors suggesting the possibility of analogous disturbances in growth control and locally invasive mechanisms. Iron plays a role in malignant cell growth, local invasion, and tumor progression, possibly due to changes in the expression of the proto-oncogene, c-myc. We hypothesized that iron plays a similar role in hemophilic synovitis. To explore this hypothesis, we investigated the in vitro effects of iron on the proliferation of a primary, human synovial fibroblast cell (HSFC) line and the involvement of c-myc in this process. We also examined the role of ceramide, a sphingolipid capable of inducing apoptosis in this model system. HSFC proliferation was increased in a dose-dependent fashion and c-myc expression was enhanced by ferric citrate compared to sodium citrate control. Ceramide prevented both the iron-induced increases in HSFC proliferation and c-myc expression. These results indicate that iron probably plays a role in the proliferative changes observed in hemophilic joint disease and that aberrant expression of c-myc may underlie the iron effects. Furthermore, these results suggest that there may be a therapeutic role for ceramide in reversing these changes.
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PMID:c-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide. 1213 May 2

One of the "signature" phenotypes of highly malignant, poorly differentiated tumors, including hepatomas, is their remarkable propensity to utilize glucose at a much higher rate than normal cells, a property frequently dependent on the marked overexpression of type II hexokinase (HKII). As the expression of the gene for this enzyme is nearly silent in liver tissue, we tested the possibility that DNA methylation/demethylation events may be involved in its regulation. Initial studies employing methylation restriction endonuclease analysis provided evidence for differential methylation patterns for the HKII gene in normal hepatocytes and hepatoma cells, the latter represented by a highly glycolytic model cell line (AS-30D). Subsequently, sequencing following sodium bisulfite treatment revealed 18 methylated CpG sites within a CpG island (-350 to +781 bp) in the hepatocyte gene but none in that of the hepatoma. In addition, treatment of a hepatocyte cell line with the DNA methyltransferase inhibitors, 5'-azacytidine and 5'-aza-2'-deoxycytidine, activated basal expression levels of HKII mRNA and protein. Finally, stably transfecting the hepatocyte cell line with DNA demethylase also resulted in activating the basal expression levels of HKII mRNA and protein. These novel observations indicate that one of the initial events in activating the HKII gene during either transformation or tumor progression may reside at the epigenetic level.
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PMID:Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression. 1256 45

The heterogeneity of cellular protein expression has stimulated development of separations targeting smaller groups of related proteins rather than entire proteomes. The following work describes the development of a technique for the characterization of membrane subproteomes from five different breast epithelial cell lines. Intact membrane proteins are separated by hydrophobicity in the first dimension using nonporous reversed-phase high-performance liquid chromatography (RP-HPLC) to generate unique chromatographic profiles. Fractions of eluent are further separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to create distinct banding patterns. This hybrid liquid phase/gel phase method circumvents issues of membrane protein precipitation and provides a simple strategy aimed at isolating and characterizing a traditionally underrepresented protein class. Membrane protein profiles are created that discriminate between microsomal fractions of breast epithelial cells in different stages of neoplastic progression. Proteins are subsequently identified using matrix-assisted laser desorption/ionization - mass spectrometry (MALDI-MS) mass fingerprinting and MALDI-quadrupole time of flight - tandem mass spectrometry (QTOF-MS/MS) peptide sequencing. Furthermore, as this strategy preserves intact protein structure, further characterization can be performed on proteins producing mass fingerprint spectra and fragmentation spectra that did not result in database protein identifications. The coupling of nonporous RP-HPLC with SDS-PAGE provides a useful alternative to two-dimensional PAGE (2-D-PAGE) for membrane protein analysis.
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PMID:Profiling the progression of cancer: separation of microsomal proteins in MCF10 breast epithelial cell lines using nonporous chromatophoresis. 1287 26

This study investigates the possible molecular basis leading to failure in a treatment that is composed of hypoxia and chemotherapy in a rat orthotopic hepatoma model. Hypoxia was induced by hepatic artery ligation, whereas chemotherapeutic effect was achieved by intraportal injection of cisplatin. High-dose sodium salicylate was administered to achieve transcriptional blockade. Significant prolongation of animal survival was observed in the groups receiving hepatic artery ligation with cisplatin or sodium salicylate. Massive tumor cell necrosis and apoptosis were found in the ligation and all of the combined treatment groups. Up-regulation of hypoxia inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at both mRNA and protein levels were detected in the groups receiving ligation and ligation with cisplatin, whereas a decreased level of von Hippel-Lindau tumor suppressor protein was identified in the group receiving ligation with cisplatin. Sodium salicylate enhanced expression of von Hippel-Lindau tumor suppressor protein but down-regulated HIF-1alpha and VEGF levels after ligation with or without cisplatin. An increased number of activated hepatic stellate cells in the tumors were observed in the ligation and ligation with cisplatin groups, whereas they were greatly reduced by sodium salicylate. In vitro study revealed that under hypoxic condition, both cisplatin and sodium salicylate could remarkably augment P53 and caspase 3 levels. Cisplatin stimulated HIF-1alpha up-regulation, whereas sodium salicylate suppressed HIF-1alpha expression. In conclusion, tumor progression after hypoxia and chemotherapy might be related to up-regulation of HIF-1alpha and subsequent VEGF production, and transcriptional blockade by sodium salicylate could enhance the therapeutic efficacy of hypoxia and chemotherapy.
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PMID:The potential role of hypoxia inducible factor 1alpha in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. 2990 84

Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na+/H+ exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na+/H+ exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in approximately 3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH2-terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.
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PMID:NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer. 1546 53

We investigated the antiproliferative effect of phenylacetate covalently linked to dextran derivatives (DMCBPA conjugates) on human breast cancer MCF-7 cells. We show that free sodium phenylacetate (NaPA) inhibits the cell growth (IC50 = 14 mM), while an important inhibitory effect is observed for DMCBPA conjugates. The IC50 dose of these conjugates is as low as 1.0 mg/ml, corresponding to 1.3 mM of phenylacetate. The precursors, dextran substituted with methylcarboxylate and benzylamide groups, did not affect the growth of MCF-7 tumor cells. We have observed that MCF-7 cell growth inhibition depends on amount of phenylacetate linked to the conjugate. The data indicated that an optimum antiproliferative effect is more significant when the amount of phenylacetate groups present on the dextran backbone is high. Analysis of doubling time by growth kinetics study shows that conjugates have more time-sustained effect than free NaPA. It is noteworthy that the inhibitory effect is observed at non-toxic concentration. Theses conjugates could be considered as acceptable derivatives to prevent tumor progression.
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PMID:Growth inhibition of MCF-7 tumor cell line by phenylacetate linked to functionalized dextran. 1555 51

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.
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PMID:Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. 1614 58


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