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)

Okadaic acid (OA), a toxin from the black sponge Halicondria okadai, is a specific inhibitor of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A). OA is a tumor promoter but also induces apoptosis in some tumor cell lines. In this study, we determined whether ras mutation and/or p53 status are characteristics associated with the cell's sensitivity to the induction of apoptosis by OA. Several cell lines that differed in ras and p53 mutations were treated with OA (10-100 nM). At 24 to 48 h after treatment, the percentage of cells undergoing apoptosis was quantitated. The cell lines with mutations in either H-ras (human bladder carcinoma cell line T24 and mouse keratinocyte cell line 308), or K-ras (human colon carcinoma cell lines DLD-1 and HCT116; human prostate cancer cell lines LNCaP and PC-3; human lung cancer cell lines Calu-6 and SKLU-1; and human pancreatic cancer cell line MIAPaCa2) were more sensitive to OA-induced apoptosis (3- to 10-fold) than the cell lines that lacked the ras mutation (mouse epidermal cell lines C50 and JB6; murine fibroblast cell line NIH3T3; human colon cancer cell line HT29; human kidney epithelial cell line Hs715.K; and human pancreatic cancer cell line Bx-PC3). Similarly, using isogenic cell lines we found that overexpression of mutated H-ras in NIH3T3 and in SV40 immortalized human uroepithelial cells (SVHUC) enhanced their sensitivity to undergo apoptosis in response to OA treatment. The T24, DLD-1, SKLU-1, Calu-6, and MIAPaCa2 cell lines express mutated p53. The SVHUC as well as their ras-transfected counterparts have inactive p53 due to complex formation between large "T" antigen and p53. Taken together, these results imply that OA-induced apoptosis may involve a p53-independent pathway. The transfectants (NIH3T3-ras and SVHUC-ras), which express mutated H-ras, have up-regulated PP2A activity. OA treatment inhibited in vivo the levels of PP1 and PP2A activity, and induced apoptosis in SVHUC-ras and other cell lines. We conclude that OA-induced cell death pathway in ras-activated cell lines may involve a cross talk between PP1 and PP2A and ras signaling pathways. In light of the present results, the current theory that OA promotes mouse skin tumor formation by selective expansion of initiated cells that harbor ras mutations needs reevaluation.
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PMID:Ras mutation, irrespective of cell type and p53 status, determines a cell's destiny to undergo apoptosis by okadaic acid, an inhibitor of protein phosphatase 1 and 2A. 1046 39

A number of recent preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved or optimized by metronomic-dosing protocols in which the drug is given at comparatively low doses using a frequent schedule of administration (e.g., once to three times per week) with no breaks, particularly when combined with an endothelial cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic drugs is particularly suitable for this type of treatment strategy. We tested one such drug, cyclophosphamide (CTX), in a protocol wherein the drug was administered to mice at low doses, of approximately 10-40 mg/kg on a daily basis through the drinking water. CTX is typically given p.o. to patients, but it has almost always been injected when treating preclinical mouse tumor models. We found p.o. CTX to be a safe and convenient treatment with significant antitumor efficacy. Growth delays were observed for human orthotopic breast or ectopic colon cancer xenografts in nude or SCID mice. Established PC3 human prostate tumor xenografts could be induced to almost fully regress, remaining virtually nonpalpable for > or =2 months of continuous therapy, after which tumors began to grow progressively. These re-emergent tumors were not found to be drug resistant when tested in new hosts, using the same treatment protocol. Regression of spontaneously arising, late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice was also observed. The effects of continuous p.o. CTX treatment were enhanced significantly in an orthotopic, metastatic breast cancer xenograft model when used in combination with an antivascular endothelial growth factor receptor-2 blocking antibody. Maximum tolerated dose levels established for other mouse strains proved highly toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were well tolerated. Taken together, the results demonstrate the feasibility of delivering CTX in a p.o. metronomic chemotherapy regimen, which proved safe, reasonably efficacious, and potentially applicable to chronic treatment. Such a regimen may be particularly well suited for integration with antiangiogenic drugs.
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PMID:Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. 1201 44

We have investigated the mitochondrial and cellular effects of the lipoxygenase inhibitor MK886. Low concentrations (1 microM) of MK886 selectively sensitized the permeability transition pore (PTP) to opening, whereas higher concentrations of MK886 (10 microM) caused depolarization through combination of an ionophoretic effect with inhibition of respiration. MK886 killed prostate cancer PC3 cells only at the higher, toxic concentration (10 microM), whereas the lower concentration (1 microM) had no major effect on cell survival. However, 1 microM MK886 alone demonstrably induced PTP-dependent mitochondrial dysfunction; and it caused cell death through the mitochondrial pathway when it was used in combination with the cyclooxygenase inhibitor, indomethacin, which had no effects per se. Treatment with 1 microM MK886 plus indomethacin sensitized cells to killing by exogenous arachidonic acid, which induces PTP opening and cytochrome c release (Scorrano, L., Penzo, D., Petronilli, V., Pagano, F., and Bernardi, P. (2001) J. Biol. Chem. 276, 12035-12040). Combination of MK886 and cyclooxygenase inhibitors may represent a viable therapeutic strategy to force cell death through the mitochondrial pathway. This approach should be specifically useful to kill cells possessing a high flux of arachidonic acid and its metabolites like prostate and colon cancer cells.
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PMID:Mitochondria are direct targets of the lipoxygenase inhibitor MK886. A strategy for cell killing by combined treatment with MK886 and cyclooxygenase inhibitors. 1208 72

We present the involvement and association of TNF-related apoptosis-inducing ligand (TRAIL) with apoptosis. Its potential application as a therapeutic agent in urologic oncology is discussed. We have examined the sensitivity of prostate carcinoma cell lines DU145, PC3 and LNCaP to TRAIL-induced apoptosis and the expression of TRAIL receptors. Furthermore we looked into the sensitization of those prostate carcinoma cell lines to TRAIL-mediated apoptosis by low toxic levels of actinomycin-D. Furthermore, we review and discuss the pertinent literature on the molecular biology of TRAIL, its receptors and future potential for therapy in urologic oncology. Recent discovery and characterization of TRAIL has led to further broadening and insights into the apoptotic process. Based on preceding in-vitro studies, the first in-vivo study using TRAIL has been conducted and published in 1999. Systemic application of TRAIL in severe combined immune deficient (SCID) mice resulted in tumor regression of subcutaneous implanted mammary and colon cancer and several groups are looking into TRAIL sensitivity of prostate cancer and renal cancer cellines. Our in-vitro data revealed a significant increase of apoptotic cell death rate following the combined application of TRAIL with actinomycin-D. Our results suggest that the combination of TRAIL and ActD may be a therapeutic option in the treatment of drug/hormone refractory prostate carcinoma. In the future TRAIL may be used in combination therapy with other immunotherapies or gene therapies providing a synergistic effect or enhancing the efficacy of chemotherapeutic or radiotherapeutic regimens.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) for treatment of prostate cancer: first results and review of the literature. 1249 68

MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.
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PMID:Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen. 1453 37

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

Hematopoietic cells (HCs) promote blood vessel formation by producing various proangiogenic cytokines and chemokines and matrix metalloproteinases. We injected mouse colon26 colon cancer cells or human PC3 prostate adenocarcinoma cells into mice and studied the localization of HCs during tumor development. HCs were distributed in the inner tumor mass in all of the tumor tissues examined; however, the localization of HCs in the tumor tissue differed depending on the tumor cell type. In the case of colon26 tumors, as the tumor grew, many mature HCs migrated into the tumor mass before fine capillary formation was observed. On the other hand, although very few HCs migrated into PC3 tumor tissue, c-Kit+ hematopoietic stem/progenitor cells accumulated around the edge of the tumor. Bone marrow suppression induced by injection of anti-c-Kit neutralizing antibody suppressed tumor angiogenesis by different mechanisms according to the tumor cell type: bone marrow suppression inhibited the initiation of sprouting angiogenesis in colon26 tumors, while it suppressed an increase in the caliber of newly developed blood vessels at the tumor edge in PC3 tumors. Our findings suggest that HCs are involved in tumor angiogenesis and regulate the angiogenic switch during tumorigenesis.
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PMID:Hematopoietic cells regulate the angiogenic switch during tumorigenesis. 1557 84

A new isoflavone 5,7,4'-trihydroxy-3'-(3-hydroxy-3-methylbutyl)isoflavone (isowigtheone hydrate) (1), together with six known isoflavones 2-7 and (-)epicatechin, were isolated from the root barks of Brosimum utile. Their structures were established on the basis of spectroscopic evidence. The in vitro cytotoxic activity of the new compound 1 was evaluated against cell lines MCF7 (human breast carcinoma), PC3 (human prostate carcinoma), HT29 (human colon cancer) and human dermis fibroblasts.
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PMID:New cytotoxic isoflavone from the root bark of Brosimum utile. 1593 38

In this paper, we will outline the current understanding of cell cycle modulation and induction of apoptosis in cancer cells by natural and synthetic bile acid. Bile acid homeostasis is tightly regulated in health, and their cellular and tissue concentrations are restricted. However, when pathophysiological processes impair their biliary secretion, hepatocytes are exposed to elevated concentrations of bile acids which trigger cell death. In this context, we developed several newly synthesized bile acid derivatives. These synthetic bile acids modulated the cell cycle and induced apoptosis in several human cancer cells similar to natural bile acids. In human breast and prostate cancer cells with different tumor suppressor p53 status, synthetic bile acid-induced growth inhibition and apoptosis were associated with up-regulation of Bax and p21(WAF1/CIP1) via a p53-independent pathway. In Jurkat human T cell leukemia cells, the synthetic bile acids induced apoptosis through caspase activation. In addition to this, the synthetic bile acids induced apoptosis in a JNK dependent manner in SiHa human cervical cancer cells, via induction of Bax and activation of caspases in PC3 prostate cancer cells and induction of G1 phase arrest in the cell cycle in HT29 colon cancer cells. Moreover, they induced apoptosis in four human glioblastoma multiform cell lines (i.e., U-118MG, U-87MG, T98G, and U-373MG) and one human TE671 medulloblastoma cells. In addition to this, a chenodeoxycholic acid derivative, called HS-1200, significantly decreased the growth of TE671 medulloblastoma tumor size and increased life span in non-obese diabetic and severe combined immunodeficient (NOD/SCID) mice. Therefore, these new synthetic bile acids, which are novel apoptosis mediators, might be applicable to the treatment of various human cancer cells.
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PMID:Modulation of the cell cycle and induction of apoptosis in human cancer cells by synthetic bile acids. 1716 73

Although 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) was reported to up-regulate death receptor 5 (DR5) protein expression and sensitize TRAIL-induced cytotoxicity, its action mechanism remains unclear. Using HCT116 colon cancer cells, we found that sensitization of TRAIL-induced cytotoxicity by 15dPGJ(2) resulted from up-regulation of DR5 via gene transcription but was not associated with PPAR-gamma activation. Moreover, 15dPGJ(2) induced GRP78, XBP1, and C/EBP homologous transcription factor (CHOP) expression in HCT116 cells, confirming that 15dPGJ(2) is an endoplasmic reticulum stress inducer. Knockdown of the CHOP gene by siRNA attenuated DR5 up-regulation and the sensitized cytotoxicity in colon cancer HCT116 and SW480. With deletion plasmids of DR5 promoters, we found that the CHOP-binding site was involved in activating the DR5 gene by 15dPGJ(2). A mechanistic study showed the contributions of reactive oxygen species (ROS) and intracellular calcium in CHOP and DR5 gene up-regulation. 15dPGJ(2) was also found to induce DR5 in two prostate cancer cell lines, LNCaP and PC3. Although in LNCaP DR5 up-regulation was accompanied by CHOP expression by 15dPGJ(2), no significant increase in CHOP expression or DR5 promoter activity was observed in PC3 cells. Intriguingly, 15dPGJ(2) induced ROS and calcium production in PC3 cells. This inability to induce CHOP was not due to the p53-null in PC3 cells, as similar extents of increase in CHOP protein were found due to 15dPGJ(2) in both wild-type and p53-null HCT116 cells. In summary, the effect of up-regulation of DR5 by 15dPGJ(2) in colon cancer cells is independent of PPAR-gamma and p53 but relies on CHOP induction through gene transcription involving ROS and calcium.
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PMID:15-deoxy-Delta12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription. 1885 46


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