Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is an anticancer prodrug that has been approved for the treatment of colon cancer. It is a member of the camptothecin class of drugs and activation to the active metabolite SN-38, is mediated by carboxylesterases (CE). SN-38 is a potent topoisomerase I poison and is highly effective at killing human tumor cells, with IC50 values in the low nM range. However, upon high dose administration of CPT-11 to cancer patients, a cholinergic syndrome is observed, that can be rapidly ameliorated by atropine. This suggests a direct interaction of the drug or its metabolites with acetylcholinesterase (AChE). Kinetic studies indicated that CPT-11 was primarily responsible for AChE inhibition with the 4-piperidinopiperidine moiety, the major determinant in the loss of enzyme activity. Structural analogs of 4-piperidinopiperidine however, did not inhibit AChE, including a benzyl piperazine derivate of CPT-11. These results suggest that novel anticancer drugs could be synthesized that do not inhibit AChE, or alternatively, that novel AChE inhibitors could be designed based around the camptothecin scaffold.
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PMID:Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11. 1625 98

The main toxicity of organophosphorus pesticides (OPs) is neurotoxicity, which is caused by the inhibition of acetylcholinesterase. OPs also affect immune responses including effects on antibody production, IL-2 production, T cell proliferation, decrease of CD5 cells, and increase of CD26 cells and autoantibodies. However, there have been few papers investigating the mechanism of OP-induced inhibition of cytolytic activity of killer cells. This study reviews the new mechanism of OP-induced inhibition of activities of natural killer (NK), lymphokine-activated killer (LAK) and cytotoxic T lymphocytes (CTL). NK, LAK and CTL induce cell death in tumor or virus-infected target cells by two main mechanisms. The first mechanism is direct release of cytolytic granules that contain perforin, granzymes, and granulysin by exocytosis to kill target cells, which is called the granule exocytosis pathway. The second mechanism is mediated by the Fas ligand (Fas-L)/Fas pathway. To date, it has been reported that OPs inhibit NK, LAK and CTL activities by at least the following three mechanisms: 1) OPs impair the granule exocytosis pathway of NK, LAK and CTL cells by inhibiting the activity of granzymes, and by decreasing the intracellular level of perforin, granzyme A and granulysin, which was mediated by inducing degranulation of NK cells and by inhibiting the transcript of mRNA of perforin, granzyme A and granulysin; 2) OPs impair the FasL/Fas pathway of NK, LAK and CTL cells, as investigated by using perforin-knockout mice, in which the granule exocytosis pathway of NK cells does not function and only the FasL/Fas pathway remains functional; 3) OPs induce apoptosis of immune cells.
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PMID:The mechanism of organophosphorus pesticide-induced inhibition of cytolytic activity of killer cells. 1689 97

Mesenchymal stem cells (MSCs) are located primarily in the bone marrow and are characterized by their capacity to differentiate into mesenchymal lineages such as bone, fat, and cartilage in response to appropriate signals. Several signaling mechanisms act to control MSC survival, proliferation, and differentiation, and failure or disruption of these signaling pathways can lead to degenerative disease or neoplasia. Organophosphate (OP) and carbamate pesticides, which are used in large amounts in agriculture to control insects, are designed to disrupt acetylcholine signaling by inhibiting the enzyme acetylcholinesterase (AChE). Effects of OP and carbamate pesticides on the human central nervous system have been well documented. However, AChE is broadly distributed, and the effects of anticholinergic insecticides on nonnervous tissue have received little attention. In the present study we found that human MSCs express AChE, which makes these cells potential targets for AChE inhibiting agents. We therefore examined the effects of an OP pesticide, chlorpyrifos, and a carbamate, carbofuran, on MSC characteristics. It was found that micromolar concentrations of these anticholinergic insecticides had no effect on MSC survival or proliferation but limited MSC differentiation capacity by inhibiting osteogenic differentiation. These results demonstrate that exposure to micromolar concentrations of OP and carbamate pesticides may affect tissue turnover and pathophysiology by interfering with MSC regulation.
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PMID:The effects of anticholinergic insecticides on human mesenchymal stem cells. 1696 32

Previous studies have shown that the cholinergic system plays a pivotal rule in small cell lung cancer (SCLC) cell growth through an autocrine loop that activates the nicotinic cholinergic receptor, which together with the activation of this receptor by nicotine links SCLC evolution with tobacco use. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is also linked to tobacco use. Here we describe the presence of molecules of the cholinergic system in NSCLC samples and cell lines and investigate the implications of the cholinergic system in cell growth regulation. Cholino-acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and acetylcholinesterase (AChE) were observed in NSCLC tumor biopsies and in NSCLC cell lines. Polymeric alkylpyridinium salts (poly-APS) are AChE inhibitors isolated from the crude extract of the marine sponge, Reniera sarai. These metabolites were characterized as a mixture of two polymers of 3-octylpyridinium, including 29 and 99 monomeric units. Exposure of normal lung fibroblast and NSCLC cell lines to poly-APS revealed a selective cytotoxicity for cancer cells as compared to the normal fibroblast cell lines. FACS analysis indicated poly-APS induced apoptosis in NSCLC cells but not in normal lymphocytes. Non-toxic doses of poly-APS also potently reduced NSCLC cell-cell adhesion in suspension cultures. The limited toxicity of poly-APS on normal cells was confirmed by injection in the caudal vein of mice. No overt effects on health parameters, such as weight gain and physical behavior, were observed, and histological analysis of major organs did not reveal differences between the treated animals as compared to controls. These data demonstrate that NSCLC cells express cholinergic molecules that may be involved in cell growth regulation and that the cholinesterase inhibitor, poly-APS, shows selective toxicity toward NSCLC cells while having no apparent toxicity towards normal cells and tissue in vitro and in vivo.
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PMID:Marine sponge-derived polymeric alkylpyridinium salts as a novel tumor chemotherapeutic targeting the cholinergic system in lung tumors. 1708 75

Environmental chemicals may be involved in the etiology of breast cancer. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones. Among these hormonal influences a leading role is attributed to the ovarian hormone estradiol, since breast cancer does not develop in the absence of ovaries. The rat mammary gland has special characteristics that make it an ideal organ for studying development, cell proliferation and transformation. In vivo and in vitro model systems for cell proliferation and mammary carcinogenesis have allowed morphological and biochemical analysis under different experimental conditions. The aim of this study was to examine the effect of eserine, an acetylcholinesterase inhibitor, as are the organophosphorous compounds malathion and parathion, and 17beta estradiol on cell proliferation and tumor formation that takes place in the rat mammary gland after in vivo and in vitro treatment. These studies showed that eserine and 17beta estradiol were capable of inducing carcinogenesis in the epithelium of rat mammary glands. It was found that there was a significant increase in the number of cells per duct of the 44-day-old rat mammary gland after the 10-day eserine treatment, compared to the control. A higher increase was observed in the animals treated for 10 days with eserine followed by 30-daily injections of estrogen in comparison to control animals. In 12 animals, two mammary tumors were directly developed in response to 17beta estradiol injected at 39 days of age with a latency period of 180 and 245 days, respectively. Such tumors were metastatic to the lung. These results suggest that terminal end buds are major targets related to rat mammary carcinogenesis and 17beta estradiol can be an initiator and promoter in this process.
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PMID:Cell proliferation and tumor formation induced by eserine, an acetylcholinesterase inhibitor, in rat mammary gland. 1714 74

Some 23 analogues of the potent acetylcholinesterase (AChE) inhibitor territrem B (1) were designed, synthesized, and tested for their biological activities. Some of the new synthetic derivatives exhibited IC50 values for AChE inhibition in the upper micromolar range. Molecular-modeling studies indicated that a planar conformation seems to be crucial for AChE inhibition. The two N-atoms of the piperazine moieties in 5o, 5p, and 5r might further enhance the inhibitory effects. The cytotoxicities of selected compounds against six human tumor cell lines were also determined.
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PMID:Design, synthesis, and biological evaluation of new territrem B analogues. 1719 4

We retrospectively evaluated clinical factors affecting long-term survival after treatment for hepatocellular carcinoma (HCC) to predict the reliability of the prognosis of patients with HCC. We analyzed 157 patients who received treatment for HCC. The prognostic index (PI) was evaluated using the Cox regression model. The overall cumulative survival rates were 79.7% at 1 year, 51.1% at 3 years, and 24.9% at 5 years. The PI was calculated by the following formula, consisting of five factors: PI = 0.637 x number of tumor lesions + 0.103 x tumor diameter + 1.003 x ascites + 0.915 x portal vein tumor thrombosis - 0.006 x cholinesterase + 2.0. It was found that liver function and progression of the tumor are the most important factors for prognosis after treatment for HCC. The PI, based on five factors, will in future be an appropriate index to predict the prognosis of patients with HCC.
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PMID:Prognostic index for survival in patients after treatment for primary hepatocellular carcinoma. 1742 Sep 50

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission, usually recognized with ocular complaints or generalized muscle weakness. However, among the 1520 MG cases that had been diagnosed and treated in our hospital in the last 15 years (1990-2005), we have identified 7 MG patients whose initial and prominent complaint was dysphonia and all had been misdiagnosed elsewhere. The diagnoses were confirmed with fibrolaryngoscope and voice analysis employed before and after a positive neostigmine (anticholinesterase) test. Electromyography with repetitive stimulations, single-fiber electromyography, and laboratory and radiographic evaluations were also conducted for diagnosis. A surprisingly low seropositivity rate of anti-acetylcholine-receptor antibodies (1/7) and anti-MuSK (Muscle Specific Kinase) antibodies (0/6) were found in these dysphonia MG patients. A cholinesterase inhibitor (ChEI) and immunosuppressive therapy were applied for treatment. Extended thymectomy was applied to MG patients with thymus hyperplasia or thymic tumor. Significant improvement was found in all 7 cases after these treatments. We have developed a sere of diagnostic protocol for this rare type of laryngeal MG, and discussed the clinical implication of our data. In summary, dysphonia or laryngeal disorder can be the only prominent manifestation of MG in rare cases, which should be taken into consideration during the diagnosis to patients with exclusive laryngeal complaints.
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PMID:Dysphonia as a primary manifestation in myasthenia gravis (MG): a retrospective review of 7 cases among 1520 MG patients. 1746 37

Hostasinine A (1), a benzylphenethylamine alkaloid with an unprecedented skeleton featuring a C-4-C-6 linkage and a nitrone moiety, was isolated from Hosta plantaginea. Its structure was established on the basis of spectroscopic data, and was further confirmed by single-crystal X-ray diffraction. The alkaloid was postulated biogenetically from haemanthidine via N-oxidation and aza-aldol-type condensation and was synthesized biomimetically. The inhibitory activities of 1 on acetylcholinesterase (AChE) and two tumor cell lines (K562 and A549) were also evaluated.
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PMID:Structure elucidation and biomimetic synthesis of hostasinine A, a new benzylphenethylamine alkaloid from Hosta plantaginea. 1799 56

Serine hydrolase KIAA1363 is an acetyl monoalkylglycerol ether (AcMAGE) hydrolase involved in tumor cell invasiveness. It is also an organophosphate (OP) insecticide-detoxifying enzyme. The key to understanding these dual properties was the use of KIAA1363 +/+ (wildtype) and -/- (gene deficient) mice to define the role of this enzyme in brain and other tissues and its effectiveness in vivo in reducing OP toxicity. KIAA1363 was the primary AcMAGE hydrolase in brain, lung, heart and kidney and was highly sensitive to inactivation by chlorpyrifos oxon (CPO) (IC50 2 nM) [the bioactivated metabolite of the major insecticide chlorpyrifos (CPF)]. Although there was no difference in hydrolysis product monoalkylglycerol ether (MAGE) levels in +/+ and -/- mouse brains in vivo, isopropyl dodecylfluorophosphonate (30 mg/kg) and CPF (100 mg/kg) resulted in 23-51% decrease in brain MAGE levels consistent with inhibition of AcMAGE hydrolase activity. On incubating +/+ and -/- brain membranes with AcMAGE and cytidine-5'-diphosphocholine, the absence of KIAA1363 activity dramatically increased de novo formation of platelet-activating factor (PAF) and lyso-PAF, signifying that metabolically-stabilized AcMAGE can be converted to this bioactive lipid in brain. On considering detoxification, KIAA1363 -/- mice were significantly more sensitive than +/+ mice to ip-administered CPF (100 mg/kg) and parathion (10 mg/kg) with increased tremoring and mortality that correlated for CPF with greater brain acetylcholinesterase inhibition. Docking AcMAGE and CPO in a KIAA1363 active site model showed similar positioning of their acetyl and trichloropyridinyl moieties, respectively. This study establishes the relevance of KIAA1363 in ether lipid metabolism and OP detoxification.
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PMID:Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification. 1816 58


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