Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diethyldithiocarbamic-acid-methyl ester (DDTC-Me) is a major metabolite of disulfiram. When given to rats, DDTC-Me was found to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) without having any effect on the high Km isoenzyme. Inhibition of low Km ALDH by DDTC-Me in vivo exhibited a dose-response relationship, with inhibition of ALDH from 11% to 90% found when DDTC-Me was administered in a dose range from 1.8 to 158 mg/kg, IP. After a single dose of DDTC-Me (41.2 mg/kg, IP), the low Km ALDH was inhibited for 168 hours suggesting an irreversible enzyme inhibition. After an ethanol challenge to DDTC-Me-treated rats, a decrease in mean arterial pressure (MAP) and increase in heart rate was observed. Decreases in MAP occurred almost immediately after ethanol challenge and remained low throughout a four hour post-ethanol period. These results suggest that in vivo administration of DDTC-Me can cause an alcohol-sensitizing reaction, and that DDTC-Me actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER.
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PMID:Diethyldithiocarbamic acid-methyl ester: a metabolite of disulfiram and its alcohol sensitizing properties in the disulfiram-ethanol reaction. 282 42

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.
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PMID:[Biomarkers of gentotoxic risk and metabolic polymorphism]. 1118 84

The present study explored the sensitivity of leukaemic blasts derived from 30 acute myeloid leukaemia (AML) patients to Bortezomib. Bortezomib induced apoptosis of primary AML blasts: 18/30 AMLs were clearly sensitive to the proapoptotic effects of Bortezomib, while the remaining cases were moderately sensitive to this molecule. The addition of tumour necrosis factor-related-apoptosis-inducing ligand, when used alone, did not induce apoptosis of AML blasts and further potentiated the cytotoxic effects of Bortezomib. The majority of AMLs sensitive to Bortezomib showed immunophenotypic features of the M4 and M5 French-American-British classification subtypes and displayed myelomonocytic features. All AMLs with mutated FLT3 were in the Bortezomib-sensitive group. Biochemical studies showed that: (i) Bortezomib activated caspase-8 and caspase-3 and decreased cellular FLICE [Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme]-inhibitory protein (c-FLIP) levels in AML blasts; (ii) high c-FLIP levels in AML blasts were associated with low Bortezomib sensitivity. Finally, analysis of the effects of Bortezomib on leukaemic cells displaying high aldehyde dehydrogenase activity suggested that this drug induced in vitro killing of leukaemic stem cells. The findings of the present study, further support the development of Bortezomib as an anti-leukaemic drug and provide simple tools to predict the sensitivity of AML cells to this drug.
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PMID:M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis. 1789 95

The cancer stem cell hypothesis proposes that cancers arise in stem/progenitor cells through disregulation of self-renewal pathways generating tumors, which are driven by a component of 'tumor-initiating cells' retaining stem cell properties. The HER2 gene is amplified in 20-30% of human breast cancers and has been implicated in mammary tumorigenesis as well as in mediating aggressive tumor growth and metastasis. We demonstrate that HER2 overexpression drives mammary carcinogenesis, tumor growth and invasion through its effects on normal and malignant mammary stem cells. HER2 overexpression in normal mammary epithelial cells (NMEC) increases the proportion of stem/progenitor cells as demonstrated by in vitro mammosphere assays and the expression of stem cell marker aldehyde dehydrogenase (ALDH) as well as by generation of hyperplastic lesions in humanized fat pads of NOD (nucleotide-binding oligomerization domain)/SCID (severe combined immunodeficient) mice. Overexpression of HER2 in a series of breast carcinoma cell lines increases the ALDH-expressing 'cancer stem cell' population which displays increased expression of stem cell regulatory genes, increased invasion in vitro and increased tumorigenesis in NOD/SCID mice. The effects of HER2 overexpression on breast cancer stem cells are blocked by trastuzumab in sensitive, but not resistant, cell lines, an effect mediated by the PI3-kinase/Akt pathway. These studies provide support for the cancer stem cell hypothesis by suggesting that the effects of HER2 amplification on carcinogenesis, tumorigenesis and invasion may be due to its effects on normal and malignant mammary stem/progenitor cells. Furthermore, the clinical efficacy of trastuzumab may relate to its ability to target the cancer stem cell population in HER2-amplified tumors.
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PMID:HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. 1859 32

Alkylphospholipids and alkylphosphocholines (APCs) are promising antitumor agents, which target the plasma membrane and affect multiple signal transduction networks. We investigated the therapeutic potential of erucylphosphohomocholine (ErPC3), the first intravenously applicable APC, in human acute myelogenous leukemia (AML) cells. ErPC3 was tested on AML cell lines, as well as AML primary cells. At short (6-12 h) incubation times, the drug blocked cells in G2/M phase of the cell cycle, whereas, at longer incubation times, it decreased survival and induced cell death by apoptosis. ErPC3 caused JNK 1/2 activation as well as ERK 1/2 dephosphorylation. Pharmacological inhibition of caspase-3 or a JNK 1/2 inhibitor peptide markedly reduced ErPC3 cytotoxicity. Protein phosphatase 2A downregulation by siRNA opposed ERK 1/2 dephosphorylation and blunted the cytotoxic effect of ErPC3. ErPC3 was cytotoxic to AML primary cells and reduced the clonogenic activity of CD34(+) leukemic cells. ErPC3 induced a significant apoptosis in the compartment (CD34(+) CD38(Low/Neg) CD123(+)) enriched in putative leukemia-initiating cells. This conclusion was supported by ErPC3 cytotoxicity on AML blasts showing high aldehyde dehydrogenase activity and on the side population of AML cell lines and blasts. These findings indicate that ErPC3 might be a promising therapeutic agent for the treatment of AML patients.
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PMID:Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms. 2020 May 57

An investigation was conducted to follow up on the apparent species-dependent toxicity reported for 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline (SGX523), a mesenchymal-epithelial transition factor (c-MET) inhibitor that entered clinical development for the treatment of solid tumors. Patients treated with SGX523 exhibited compromised renal function presumably resulting from crystal deposits in renal tubules. Our independent metabo'lite profiling of SGX523 indicates that a major NADPH-independent, late-eluting metabolite [6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin-2(1H)-one (M11)] was generated by monkey and human liver S-9, and to a lesser extent by rat S-9, whereas M11 was absent in dog S-9 incubations. We confirmed the identity of M11 as 2-quinolinone-SGX523. Experiments with various molybdenum hydroxylase inhibitors showed that aldehyde oxidase (AO), and not xanthine oxidase, metabolized SGX523 to M11 in monkey and human liver cytosol. In addition, the oxygen incorporated into M11 was derived from water rather than atmospheric oxygen, corroborating M11 formation via AO. After oral dosing in monkeys, metabolite profiling of plasma and urine showed that SGX523 was indeed metabolized to M11 and its N-demethyl analog (M8). In urine, M11 levels were approximately 70-fold greater than that of SGX523, and the solubility of M11 in urine was only 3% of that of SGX523. In summary, SGX523 is metabolized by AO in a species-specific manner to a markedly less-soluble metabolite, M11. We propose that M11 is likely involved in the observed obstructive nephropathy reported in clinical studies. Moreover, this study illustrates the need to conduct thorough metabolic evaluations early in drug development to select the most relevant nonclinical species for toxicological evaluation.
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PMID:Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications. 2042 47

In this chapter we provide an overview of stem cells in normal tissues as well as in many different types of cancers. All tissues in the body are derived from organ-specific stem cells that retain the ability to self-renew and differentiate into specific cell types. The cancer stem cell hypothesis suggests that tumors arise from cell populations with dysregulated self-renewal. This may be tissue stem cells or more differentiated cells that acquire self-renewal capabilities. In addition, we outline some useful assays for purification and isolation of cancer stem cells including the dye exclusion side population assay, flow cytometry sorting techniques for identification of putative cancer stem cell markers, tumorspheres assay, aldehyde dehydrogenase activity assay, PKH, and other membrane staining used to label the cancer stem cells, as well as in vivo xenograft transplantation assays. We also examine some of the cell signaling pathways that regulate stem cell self-renewal including the Notch, Hedgehog, HER2/PI3K/Akt/PTEN, and p53 pathways. We also review information demonstrating the involvement of the microenvironment or stem cell niche and its effects on the growth and maintenance of cancer stem cells. Finally, we highlight the therapeutic implications of targeting stem cells by inhibiting these pathways for the treatment and prevention of cancer.
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PMID:Stem cells in normal development and cancer. 2107 31

Reactive oxygen species increases in various diseases including cancer and has been associated with induction of epithelial-mesenchymal transition (EMT), as evidenced by decrease in cell adhesion-associated molecules like E-cadherin, and increase in mesenchymal markers like vimentin. We investigated the molecular mechanisms by which Snail transcription factor, an inducer of EMT, promotes tumor aggressiveness utilizing ARCaP prostate cancer cell line. An EMT model created by Snail overexpression in ARCaP cells was associated with decreased E-cadherin and increased vimentin. Moreover, Snail-expressing cells displayed increased concentration of reactive oxygen species (ROS), specifically, superoxide and hydrogen peroxide, in vitro and in vivo. Real Time PCR profiling demonstrated increased expression of oxidative stress-responsive genes, such as aldehyde oxidase I, in response to Snail. The ROS scavenger, N-acetyl cysteine partially reversed Snail-mediated EMT after 7 days characterized by increased E-cadherin levels and decreased ERK activity, while treatment with the MEK inhibitor, UO126, resulted in a more marked effect by 3 days, characterized by cells returning back to the epithelial morphology and increased E-cadherin. In conclusion, this study shows for the first time that Snail transcription factor can regulate oxidative stress enzymes and increase ROS-mediated EMT regulated in part by ERK activation. Therefore, Snail may be an attractive molecule for therapeutic targeting to prevent tumor progression in human prostate cancer.
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PMID:Snail-mediated regulation of reactive oxygen species in ARCaP human prostate cancer cells. 2109 14

The Toll/TLR receptor family plays a central role in both vertebrate and insect immunity, driving the activation of humoral immunity in response to pathogens. In Drosophila, Toll is also responsible for directing the formation of the Dorsal/NFkappaB gradient specifying dorsoventral patterning of the embryo. Two recent studies have revealed that endocytosis and elements of the molecular machinery governing endosomal progression are required for Drosophila Toll signaling in development and immunity. We demonstrated that Toll is not only present at the plasma membrane but also in a Rab5(+) early endosomal compartment in the embryo and that the distribution of constitutively active Toll(10B) is shifted towards endosomes. Localized inhibition of Rab5 function on the ventral side leads to a reduction of nuclear Dorsal levels, while locally increasing Rab5 function leads to potentiation of signaling. Independently, another laboratory identified the endosomal protein Mop as a potentiator of Toll signaling in Drosophila cell culture and fat-body tissue. Mop functions together with the ESCRT 0 component, Hrs, previously reported to stimulate endosomal progression and the signaling ability of internalized EGFR. We discuss these studies and briefly summarize the most significant findings concerning the role of intracellular localization and trafficking in mammalian TLR function.
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PMID:Regulation of Toll and Toll-like receptor signaling by the endocytic pathway. 2177 9

Cumulative evidence has demonstrated the presence of cancer stem cells (CSC) in breast cancer and its putative role in cancer progression. Nonetheless, the clinical significance of CSC in breast cancer remains elusive. The underlying reasons could be due to the heterogeneity of breast cancer subtypes as well as different markers used to define breast CSC. In this study, three widely used markers (aldehyde dehydrogenase (ALDH)1+ and CD24-CD44+) were used to define two populations of CSC in a large cohort of breast cancers. The expressions of these markers were correlated with different clinicopathological features and the molecular subtypes. ALDH1+ breast cancers were associated with basal-like and HER2-overexpressing subtypes and the characteristics histologic features were related to these two subtypes. On the other hand, CD24-CD44+ breast cancers were associated positively with the presence of extensive in situ component, the absence of lymph node involvement, and basal markers, but negatively with HER2. CD24-CD44+ breast cancers were also positively associated with luminal B cancers. As the expression of CSC markers varied among different molecular subtypes and different clinicopathological features, it appeared that each CSC population could have distinct clinical values in different subgroups of breast cancers. For improved prognostication with CSC, combining the analysis of CSC markers would be required. Within the luminal cancers, CSC appeared to identify cancers with poor outcome. The presence of CSC populations was associated with ER-PR+ cancers and tumors expressing basal markers. Basal marker expression can complement with CSC for improved indicator for poor prognosis in luminal breast cancers. For the first time, the possible contribution of CSC to these aggressive luminal cancers was demonstrated. The association of basal features and CSC in luminal cancers also raised the possibility that luminal cancer cells may acquire basal phenotype and CSC properties together during their progression.
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PMID:Cancer stem cell markers are associated with adverse biomarker profiles and molecular subtypes of breast cancer. 2305 57


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