Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been reported that not only endogenous nitric oxide (NO) but also carbon monoxide (CO) produced by heme oxygenase (HO) have many physiological functions. The objective of the present study was to determine whether endogenous NO or CO is involved in the experimental pulmonary or liver metastasis of colon cancer in mice. Intravenous or intrasplenic injection of colon 26 cells from a mouse colon adenocarcinoma cell line resulted in multiple pulmonary or liver metastases. NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase (NOS), or zinc deuteroporphyrin 2, 4-bis glycol (ZnDPBG), a competitive inhibitor of HO, was administered to the mice only on the day of tumor inoculation. We assessed the number of tumor cells 24 h later and the outcome of metastases of the target organ. In the pulmonary metastasis model, L-NAME increased both the number of tumor cells 24 h later and outcome of metastases 18 days later, but did not have a significant effect on liver metastasis. On the other hand, metastasis to the liver, but not that to the lung, increased following administration of ZnDPBG. These results suggest that the activities of NOS and HO could influence experimental metastasis in an organ-specific manner.
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PMID:Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice. 1452 34

Hypermethylation of CpG islands in the promoter regions is an important mechanism to silence the expression of many important genes in cancer. The hypermethylation status is passed to the daughter cells through the methylation of the newly synthesized DNA strand by 5-cytosine DNA methyltransferase (DNMT). We report herein that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea, can inhibit DNMT activity and reactivate methylation-silenced genes in cancer cells. With nuclear extracts as the enzyme source and polydeoxyinosine-deoxycytosine as the substrate, EGCG dose-dependently inhibited DNMT activity, showing competitive inhibition with a K(i) of 6.89 microM. Studies with structural analogues of EGCG suggest the importance of D and B ring structures in the inhibitory activity. Molecular modeling studies also support this conclusion, and suggest that EGCG can form hydrogen bonds with Pro(1223), Glu(1265), Cys(1225), Ser(1229), and Arg(1309) in the catalytic pocket of DNMT. Treatment of human esophageal cancer KYSE 510 cells with 5-50 microM of EGCG for 12-144 h caused a concentration- and time-dependent reversal of hypermethylation of p16(INK4a), retinoic acid receptor beta (RARbeta), O(6)-methylguanine methyltransferase (MGMT), and human mutL homologue 1 (hMLH1) genes as determined by the appearance of the unmethylation-specific bands in PCR. This was accompanied by the expression of mRNA of these genes as determined by reverse transcription-PCR. The re-expression of RARbeta and hMLH1 proteins by EGCG was demonstrated by Western blot. Reactivation of some methylation-silenced genes by EGCG was also demonstrated in human colon cancer HT-29 cells, esophageal cancer KYSE 150 cells, and prostate cancer PC3 cells. The results demonstrate for the first time the inhibition of DNA methylation by a commonly consumed dietary constituent and suggest the potential use of EGCG for the prevention or reversal of related gene-silencing in the prevention of carcinogenesis.
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PMID:Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. 1463 67

The efficacy of antineoplastic compounds can depend heavily on the genetic background of the cells exposed to the drugs. This becomes evident by the fact that HT-29 human colon cancer cells but not primary murine nontransformed colonocytes are efficiently submitted to apoptosis by the flavonoid flavone. By determining caspase-3 activation, plasma membrane disintegration, and nuclear fragmentation, we show here that flavone also does not promote apoptosis in preneoplastic NCOL-1 colonocytes derived from a nontransformed human biopsy specimen. In clear contrast, the antitumor drug camptothecin potently induces apoptosis in NCOL-1 cells associated with a specific down-regulation of the antiapoptotic factor bcl-XL at the mRNA and protein levels and with the activation of the mitochondrial apoptosis pathway. Confocal microscopy revealed an increased production of superoxide anion radicals in the mitochondria of NCOL-1 cells that preceded the apoptotic events. However, in the case of flavone, the mitochondrial oxygen radicals were effectively scavenged by physiological concentrations of nitric oxide (NO), whereas in the case of camptothecin, the available nitric oxide was rapidly scavenged by the production of large quantities of cytosolic superoxide anions. Increasing the levels of nitric oxide inside NCOL-1 cells by sodium nitroprusside prevented the apoptosis induction by camptothecin. Reducing the levels of nitric oxide by using the NO synthase inhibitor, Nomega-nitro-l-arginine methyl ester in NCOL-1 cells or using HT-29 cells that intrinsically have low NO levels enabled flavone to trigger the apoptosis pathway. In conclusion, our studies demonstrate that the intracellular levels of nitric oxide significantly change the apoptotic response to antineoplastic agents in colonic cells.
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PMID:Nitric oxide levels in human preneoplastic colonocytes determine their susceptibility toward antineoplastic agents. 1464 80

Human endostatin has an internal Asn-Gly-Arg (NGR) motif at position 126-128 following a proline at position 125. Asn-Gly-Arg-containing peptides have been shown to target tumour vasculature and inhibit aminopeptidase N activity. We previously compared the in vitro and in vivo biological activities of native endostatin and endostatin with a proline to alanine mutation (P125A-endostatin). P125A-endostatin exhibited greater inhibition of both endothelial cell proliferation and human ovarian cancer growth compared to native endostatin. Here we explore further the effects on biological activity of the P125A mutation, and show that aminopeptidase N is not involved. To determine whether the increased biological activity of the mutant was due to unmasking of downstream NGR-sequence, effect of endostatin on aminopeptidase N activity was investigated. Neither the native nor the P125A-endostatin inhibited aminopeptidase N. However, synthetic peptides consisting of the S118-T131 region of endostatin inhibited aminopeptidase N. These results suggest that the internal NGR site in native or mutant endostatin is not accessible to aminopeptidase N, and that this activity is not involved in the enhanced biological activity of the P125A form. P125A-endostatin bound to endothelial cells more efficiently than native endostatin and exhibited greater inhibition of not only proliferation but also migration of endothelial cells. P125A-endostatin also localised into tumour tissue to a higher degree than the native protein, and displayed greater inhibition of growth of colon cancer in athymic mice. Both proteins inhibited tumour cell-induced angiogenesis effectively. Real-time PCR analysis showed that both native and P125A-endostatin decreased expression of key proangiogenic growth factors. Vascular endothelial growth factor and angiopoietin 1 were downregulated more by the mutant. These studies suggest that the region around P125 can be modified to improve the biological activity of endostatin.
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PMID:Improved biological activity of a mutant endostatin containing a single amino-acid substitution. 1508 96

Three human Escherichia coli heat-stable peptide (STh) analogues, each containing a DOTA chelating group, were synthesized by SPPS and oxidative refolding and compared in in vitro and in vivo systems. One analogue, DOTA-F19-STh(1-19), contains an N-terminal DOTA group attached via an amide bond linkage to an STh moiety which is essentially wild-type except for a Tyr to Phe alteration at position 19 of the molecule. A second analogue, DOTA-R1,4,F19-STh(1-19), differs from the first in that asparagine residues in positions 1 and 4 have been altered to arginine residues in order to examine the effect of positively charged groups in the linker domain. A third analogue, DOTA-11AUN-F19-STh(1-19), differs from the first in that it incorporates an 11-aminoundecanoic acid spacer group between the DOTA group and the first asparagine residue. In vitro competitive binding assays utilizing T-84 human colon cancer cells demonstrated that significant alterations to the N-terminal region of the STh molecule were well tolerated and did not significantly affect binding affinity of STh for the guanylyl cyclase C (GC-C) receptor. Internalization and efflux studies of the indium-labeled species demonstrated that inclusion of positive charge in the linker moiety inhibits internalization of the compound within tumor cells. The characteristics of the three analogues were compared in an in vivo model utilizing T-84 human colon cancer cell xenografts in SCID mice. Clearance of all analogues was rapid, primarily via renal excretion into the urine, with >89% ID excreted into the urine at 1 h pi for all analogues. The 111In-DOTA-R1,4,F19-STh(1-19) and 111In-DOTA-11AUN-F19-STh(1-19) analogues both had longer residence times in the blood than did the 111In-DOTA-F19-STh(1-19) analogue, probably accounting for increased %ID/g values for tumors and nontarget tissues at 1 h pi. At 4 h pi, significant differences between analogues were only seen with respect to metabolic routes of excretion, indicating that increased blood residence time did not result in increased tumor residualization. Reduction of hepatic uptake of these compounds, however, could have significance in the development of agents for the imaging of hepatic metastases. The ability to manipulate in vivo pharmacodynamics and tumor uptake of radiolabeled STh peptides through modification of linker moieties is under continuing investigation in order to produce optimal imaging and therapeutic radiopharmaceuticals.
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PMID:In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties. 1526 76

Tumor vasculatures express high levels of alphaVbeta3/alphaVbeta5 and alpha5beta1 integrins. Consequently, peptides containing the RGD (Arg-Gly-Asp) sequence, which is present in ligands of integrins, is effective in targeting therapeutic reagents to tumor vascular endothelium. In our study, we investigated whether the biologic activity of endostatin can be enhanced by the addition of an integrin targeting sequence. RGD sequence was added to either the amino or carboxyl terminus of endostatin containing a point mutation, P125A-endostatin. Earlier we have shown that the P125A mutation did not affect the biologic activity of endostatin but in fact had better antiangiogenic activity when compared to the native molecule. Further modification of P125A-endostatin with the RGD motif showed specific and increased binding to endothelial cells, and the increased binding coincided with improved antiangiogenic properties. Both amino and carboxyl terminal RGD-modification of P125A-endostatin resulted in greater inhibition of endothelial cell migration and proliferation. RGD modification increased tumor localization without affecting the circulatory half-life of P125A-endostatin, and RGD-modified P125A-endostatin was found to be more effective when compared to the P125A-endostatin in inhibiting ovarian and colon cancer growth in athymic mice. Complete inhibition of ovarian tumor growth was observed when P125A-endostatin-RGD was encapsulated into alginate beads. These studies demonstrate that addition of a vascular targeting sequence can enhance the biologic activity of an antiangiogenic molecule.
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PMID:Addition of integrin binding sequence to a mutant human endostatin improves inhibition of tumor growth. 1530 Jul 95

SR (serine-arginine) proteins are essential pre-mRNA splicing factors. Several SR proteins have been characterized in humans, among them SR-A1. It has been demonstrated by members of our group that the SR-A1 gene is constitutively expressed in most of the human tissues, while its transcription is increased in breast carcinoma cell lines. Moreover, the SR-A1 gene is overexpressed in a set of ovarian tumors, suggesting that it may be involved in the pathogenesis and/or progression of ovarian cancer. Therefore, in the present study we examined the expression of the SR-A1 gene in colon cancer tissues by RT-PCR and found that it is overexpressed as compared to normal mucosa (p=0.01). The SR-A1 gene was expressed more frequently in well-differentiated tumors than those with poor differentiation. Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that SR-A1-positivity is associated with a long survival (p=0.044). However, when entered into a Cox multivariate model adjusted for other clinicopathological features studied, SR-A1 expression status was not found to be of independent prognostic significance. To the best of our knowledge, this is the first study examining the expression of the novel gene SR-A1 in colon cancer progression.
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PMID:SR-A1, a member of the human pre-mRNA splicing factor family, and its expression in colon cancer progression. 1549 72

Colorectal cancer is the second most deadly cancer in the United States. When diagnosed early, current treatments bring a limited success; however, once metastasis occurs, radiation and chemotherapy are generally ineffective. Structural changes in the ECM are necessary for cell migration during tissue remodeling. Matrix metalloproteinases (MMPs), VEGF, Ki-67 (proliferative protein), and constituents of ECM, such as fibronectin, play a critical role in angiogenesis and are thus crucial in neoplastic invasion and metastasis. Based on antitumor properties of certain nutrients, we investigated the effect of a diet containing lysine, proline, arginine, ascorbic acid, and green tea extract (NM) on the growth of tumors, induced by implanting human colon HCT 116 cancer cells in athymic nude mice, and the expression of MMPs, VEGF, Ki-67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). After one week of isolation, 5 to 6 week-old athymic male nude mice (n=12) were inoculated with 3x10(6) colon cancer HCT 116 cells. After injection, the mice were randomly divided into 2 groups; group A was fed a regular diet and group B was fed a regular diet supplemented with 0.5% NM. The mice were sacrificed 4 weeks later, and their tumors were excised, weighed, and processed for histology. Results showed that the nutrient mixture (NM) inhibited growth and reduced the size of tumors in nude mice. Furthermore, histological evaluation revealed increased mitotic index, MMP-9 and VEGF secretion and reduced basement membrane in the control group tissues. Nutrient supplementation strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting the nutrient combination has potential as an anticancer agent. Histological studies supported these findings by showing inhibition of MMP-9 and VEGF secretion and mitotic index, which are critical parameters for cancer control and prevention.
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PMID:In vivo antitumor effect of ascorbic acid, lysine, proline and green tea extract on human colon cancer cell HCT 116 xenografts in nude mice: evaluation of tumor growth and immunohistochemistry. 1570 10

Infection with mycoplasma is a common problem in cell cultures, with Mycoplasma hyorhinis being the predominant species. Here we investigate the effect of M. hyorhinis infection on L-arginine metabolism, with focus on iNOS-mediated NO synthesis in murine keratinocytes and the human colon cancer cell line DLD-1. iNOS and arginase are L-arginine-metabolizing enzymes involved in the regulation of inflammatory processes, with NO contributing to innate immunity. In murine cells, M. hyorhinis infection enhances cytokine-induced iNOS expression and augments iNOS activity, whereas in the absence of cytokines it causes de novo induction of iNOS mRNA without subsequent translation into iNOS protein. In turn, arginase-1 mRNA expression is diminished in M. hyorhinis-infected murine keratinocytes, resulting in decreased arginase activity. One of the underlying upstream mechanisms is NF-kappaB activation. In contrast, in human cells neither iNOS mRNA nor protein expression is affected by M. hyorhinis infection, but NO synthesis is enhanced, which may be caused by increased L-arginine import. This demonstrates that infection with M. hyorhinis leads to different effects on gene regulation of the murine and human iNOS gene. Our study underlines the importance of routine checking of cell cultures for mycoplasma contamination, particularly in studies on NO-mediated effects or inflammatory processes.
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PMID:Impact of Mycoplasma hyorhinis infection on L-arginine metabolism: differential regulation of the human and murine iNOS gene. 1621 77

Pemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non-small cell lung cancer, is an excellent substrate for the reduced folate carrier (RFC). To explore the carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis and PT632 selective pressure. A clone (PT1) was obtained with a glycine to arginine substitution at amino acid 401, resulting in the loss of RFC function. PT1 cells were resistant to PT632 (178-fold), methotrexate (4-fold), and ZD1694 (Tomudex, raltitrexed; 20-fold), but were 3-fold collaterally sensitive to pemetrexed when grown in 25 nmol/L of 5-formyltetrahydrofolate. PT1 cells transfected with wild-type RFC had antifolate sensitivities comparable to that of wild-type HCT-15 cells, indicating that the RFC mutation was the sole basis for resistance. Folate pools were contracted in PT1 cells by 32% or 60%, as measured by radiolabeling intracellular folates or by an enzyme binding assay, respectively. This was reflected in marked (6.5-fold) collateral sensitivity to trimetrexate. The initial uptake of pemetrexed in PT1 cells was markedly reduced ( approximately 85%) but intracellular pemetrexed levels increased to approximately 60% and approximately 70% to that of wild-type cells after 2 hours and 6 days, respectively. There was increased pemetrexed inhibition of glycinamide ribonucleotide transformylase and, to a lesser extent, thymidylate synthase in PT1 cells growing in 5-formyltetrahydrofolate based on nucleoside protection analyses. Hence, loss of RFC function leads to collateral sensitivity to pemetrexed in HCT-15 cells, likely due to cellular folate pool contraction resulting in partial preservation of pemetrexed polyglutamylation and increased target enzyme inhibition. micro
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PMID:The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. 1650 19


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