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)

Flavone 8-acetic acid (FAA) is a new experimental antitumor drug with activity against various murine and human solid tumors in vitro and in vivo. We previously demonstrated that FAA suppressed the growth of a human colon cancer cell line (HCT-116). In this study we investigated the effect of FAA on human peripheral blood (PBL) and human colonic lamina propria lymphocyte (LPL) DNA synthesis. Our results show that FAA inhibited DNA synthesis in PBL and LPL in a dose-dependent fashion. In addition, FAA inhibited the activity of the intracellular enzyme, ornithine decarboxylase (ODC), in stimulated PBL and LPL. FAA did not inhibit phorbol ester (PDB) and calcium ionophor(ionomycin)-stimulated LPL DNA synthesis. These results suggest that FAA alters DNA synthesis of human peripheral and colonic mucosal lymphocytes. We postulate that FAA may affect the human peripheral and mucosal immune system.
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PMID:Flavone acetic acid suppresses human peripheral blood lymphocyte and human colonic lamina propria lymphocyte DNA synthesis. 239 38

Flavonoids are found in many food items of plant origin. Intake of flavonoids has been linked to the prevention of human diseases including cancer. However, little is known about the intestinal absorption of flavonoids in the cellular level. This study was designed to study the absorption of dietary flavonoids using cultured human intestinal epithelial cell monolayer as a model system and 14C-flavone as a model compound. 14C-flavone at 10 microM was found to move across the cell monolayer rapidly both from the luminal to basolateral direction and from the basolateral to luminal direction. The rate of transport from the luminal to basolateral direction was 5 times of the rate for phenylalanine, an aromatic amino acid. Flavone also accumulated substantially in the cells. Replacing sodium in the transport buffer with potassium did not affect the transport but reducing the incubation temperature significantly decreased the initial rate of transport. The presence of protein in the transport buffer reduced the initial rate of transport to half. Other flavonoids and hydrophobic chemicals at 100 microM had no effects on the transport. Together with the evidence from microscopic observation (Cancer Letts. 110: 41-48, 1996), this study supports that rapid diffusional transport may be the main route for flavonoid absorption. The ability of intestinal cells to accumulate flavone is consistent with the role of flavonoids in colon cancer prevention.
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PMID:Transepithelial transport and accumulation of flavone in human intestinal Caco-2 cells. 987 22

Flavonoids are polyphenolic compounds that occur ubiquitously in plants. They are discussed to represent cancer preventive food components in a human diet that is rich in fruits and vegetables. To understand the molecular basis of the putative anticancer activity of flavonoids, we investigated whether and how the core structure of the flavones, 2-phenyl-4H-1-benzopyran-4-one (flavone) affects proliferation, differentiation, and apoptosis in HT-29 human colon cancer cells. Moreover, the effects of flavone in transformed epithelial cells were compared with those obtained in nontransformed primary mouse colonocytes. Proliferation, differentiation, and apoptosis in transformed as well as nontransformed colon cells were measured by fluorescence-based techniques. Apoptosis was also determined by changes in membrane permeability, FACScan analysis, and detection of DNA fragmentation. Semiquantitative reverse transcription PCR was performed to assess the effects of flavone on transcript levels. Flavone was found to reduce cell proliferation in HT-29 cells with an EC(50) value of 54.8 +/- 1.3 microM and to potently induce differentiation as well as apoptosis. The flavonoid proved to be a stronger apoptosis inducer than the clinically established antitumor agent camptothecin. The effects of flavone in HT-29 cells were associated with changed mRNA levels of cell-cycle- and apoptosis-related genes including cyclooxygenase-2 (COX-2), nuclear transcription factor kappaB (NF-kappaB), and bcl-X(L). Moreover, flavone, but not camptothecin, displayed a high selectivity for the induction of apoptosis and of growth inhibition only in the transformed colonocytes. In conclusion, the plant polyphenol flavone induces effectively programmed cell death, differentiation, and growth inhibition in transformed colonocytes by acting at the mRNA levels of genes involved in these processes. Because these genes play a crucial role in colon carcinogenesis, flavone may prove to be a potent new cytostatic compound with improved selectivity toward transformed cells.
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PMID:Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. 1091 56

Lactate production from glucose even in the presence of oxygen is a characteristic of cancer cell metabolism and an important feature for tumor progression. Here, we describe that an increased uptake of lactate into mitochondria of HT-29 human colon cancer cells by treatment of cells with the flavonoid flavone is associated with an increased production of mitochondrial superoxide anions and apoptotic cell death. In search of the mitochondrial transporter that could promote enhanced lactate uptake and energetic flow through the electron transport chain, we used fluorescein as a model substrate. Flavone increased fluorescein uptake at pH 7.4 into mitochondria of HT-29 cells almost tenfold while lactate inhibited uptake significantly. Uptake of fluorescein in the absence or presence of flavone was strongly increased by lowering pH from 7.4 to 6.0 and almost abolished by the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP). The lactate-sensitive part of fluorescein transport was completely blocked by p-chloromercuribenzenesulfonic acid (pCMBS), a specific inhibitor of the monocarboxylate transporter-1 (MCT-1) that by Western blotting and immunofluorescence was identified in mitochondria of HT-29 cells. Finally, lactate increased and pCMBS inhibited the flavone-induced generation of mitochondrial O2-* radicals and in turn blunted the apoptotic response. In conclusion, our studies provide evidence that flavone reverts the metabolic phenotype of transformed colonocytes towards a phenotype characteristic for normal cells. Transformed colonocytes, however, seem especially vulnerable to O2-*, produced in mitochondria as a consequence of these metabolic alterations, and respond with the induction of apoptosis.
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PMID:Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells. 1545 31

There is emerging evidence that dietary factors can prevent cancer by affecting the process of carcinogenesis. Flavonoids present in vegetarian food possess antioxidant activities, have scavenging effects on activated carcinogens and mutagens, affect cell cycle progression and alter gene and protein expression. We report here that flavone, the core structure of the flavone subgroup, potently inhibits proliferation and induces apoptosis in HCT-116 colon cancer cells. Flavone induces the activation of caspases 2, 3, 8, 9 and 10 and a decrease of mitochondrial anti-apoptotic Bcl(2) protein expression. Further analysis revealed that caspase 10 activation is mediated via caspase 1. Additionally, treatment with flavone results in release of the mitochondrial apoptosis-inducing factor (AIF), the key trigger of caspase-independent apoptosis, into the cytosol. In summary, our data show that flavone induces apoptosis in a caspase-dependent and -independent manner.
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PMID:Flavone initiates a hierarchical activation of the caspase-cascade in colon cancer cells. 1590 22

Colorectal cancer is the second leading cause of cancer deaths worldwide with diet playing a prominent role in disease initiation and progression. Flavonoids are secondary plant compounds that are suggested as protective ingredients of a diet rich in fruits and vegetables. We here tested whether flavone, a flavonoid that proved to be an effective apoptosis inducer in colon cancer cells in culture, can affect the development of aberrant crypt foci (ACFs) in C57BL/6J mice in vivo when preneoplastic lesions were induced by the carcinogen 1,2-dimethylhydrazine (DMH). Flavone applied at either a low dose (15 mg/kg body wt per day) or a high dose (400 mg/kg body wt per day) reduced the numbers of ACFs significantly, independent of whether it was supplied simultaneously with the carcinogen (blocking group) or subsequent to the tumor induction phase (suppressing group). Proteome analysis performed in colonic tissue samples revealed that flavone treatment increased the expression of a number of Krebs cycle enzymes in the suppressing group and this was associated with reduced crypt multiplicity. It suggests that mitochondrial substrate oxidation is increased by flavone in colonic cells in vivo as already observed in HT-29 cells in vitro as the prime mechanism underlying tumor cell apoptosis induction by flavone. In conclusion, flavone reduces the number of ACFs in DMH-treated mice at doses that can be achieved for flavonoids by a diet rich in fruits and vegetables. Moreover, reduction in crypt multiplicity by flavone is most probably due to the preservation of a normal oxidative metabolism.
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PMID:The suppression of aberrant crypt multiplicity in colonic tissue of 1,2-dimethylhydrazine-treated C57BL/6J mice by dietary flavone is associated with an increased expression of Krebs cycle enzymes. 1734 40

Flavone and camptothecin were both shown to potently induce apoptosis in HT-29 human colon cancer cells. Whereas camptothecin acts on the basis of topoisomerase-I inhibition, flavone appears to burst mitochondrial production of reactive oxygen species by increasing respiratory chain activity. In our study, we searched for similarities and differences in the proteome response of HT-29 cells when treated with the two different compounds. The accessible proteome of HT-29 cells was separated subsequent to the exposure to flavone or camptothecin by 2D-polyacrylamide-gel electrophoresis using pH-gradients between 4 and 7 and 6 and 11 in the first dimension and proteins with changed expression level were identified by peptide mass fingerprints of tryptic digests of the protein spots. Whereas there was a high congruence with regard to the identities of regulated proteins and their grade of regulation, a number of spots changed specifically only in response to either flavone or camptothecin. Nuclear envelope proteins were specifically increased by camptothecin indicating the intervention of this drug with cell division processes. Increased levels of coproporphyrinogen III oxidase, involved in cytochrome synthesis, and ubiquinol-cytochrome-c reductase suggest adaptations to flavone in order to enable a higher substrate flux through the respiratory chain. In conclusion, HT-29 cells respond to camptothecin and flavone with regulations of many proteins in a similar manner suggesting those alterations to be caused by apoptosis induction. Some protein regulations, however, were specific for each compound and point to the mechanism of their action.
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PMID:Proteome response in HT-29 human colorectal cancer cells to two apoptosis-inducing compounds with different mode of action. 1821 53

In the present article, we have synthesized a combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, (1)H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-alpha and IL-6. Out of 15 compounds screened, 2a and 2d exhibited promising anticancer activity (61-73% at 10 microM concentration) against all selected cell lines and IL-6 inhibition (47% and 42% at 10 microM concentration) as in comparison to standard flavopiridol (72-87% inhibition at 0.5 microM) and dexamethasone (85% inhibition at 1 microM concentration), respectively. Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Out of 15, four 3,5-diaryl pyrazole derivatives exhibiting potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. The IC(50) values of compounds (2a, 2d, 2h and 2l) for monophenolase inhibition were determined to range between 1.5 and 30 microM. Compounds 2a, 2d, 2h and 2l also inhibited diphenolase significantly with IC(50) values of 29.4, 21.5, 2.84 and 19.6 microM, respectively. All four 3,5-diaryl pyrazole derivatives were active as tyrosinase inhibitors (2a, 2d, 2h and 2l), and belonging to competitive inhibitors. Interestingly, they all manifested simple reversible slow-binding inhibition against diphenolase.
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PMID:Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer, anti-inflammatory agents. 2063 87

Apoptosis can be triggered in two different ways, through the intrinsic or the extrinsic pathway. The intrinsic pathway is mediated by the mitochondria via the release of cytochrome C while the extrinsic pathway is prompted by death receptor signals and bypasses the mitochondria. These two pathways are closely related to cell proliferation and survival signaling cascades, which thereby constitute possible targets for cancer therapy. In previous studies we introduced two plant derived isomeric flavonoids, flavone A and flavone B which induce apoptosis in highly tumorigenic cancer cells of the breast, colon, pancreas, and the prostate. Flavone A displayed potent cytotoxic activity against more differentiated carcinomas of the colon (CaCo-2) and the pancreas (Panc28), whereas flavone B cytotoxic action is observed on poorly differentiated carcinomas of the colon (HCT 116) and pancreas (MIA PaCa). Apoptosis is induced by flavone A in better differentiated colon cancer CaCo-2 and pancreatic cancer Panc 28 cells via the intrinsic pathway by the inhibition of the activated forms of extracellular signal-regulated kinase (ERK) and pS6, and subsequent loss of phosphorylation of Bcl-2 associated death promoter (BAD) protein, while apoptosis is triggered by flavone B in poorly differentiated colon cancer HCT 116 and MIA PaCa pancreatic cancer cells through the extrinsic pathway with the concomitant upregulation of the phosphorylated forms of ERK and c-JUN at serine 73. These changes in protein levels ultimately lead to activation of apoptosis, without the involvement of AKT.
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PMID:Mechanism of Action of Two Flavone Isomers Targeting Cancer Cells with Varying Cell Differentiation Status. 2660 69