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

The anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino-]carbonyloxycamptothecin (CPT-11) is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. It is hydrolyzed by carboxylesterases to yield 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I poison. However, upon high-dose intravenous administration of CPT-11, a cholinergic syndrome is observed that can be ameliorated by atropine. Previous studies have indicated that CPT-11 can inhibit acetylcholinesterase (AChE), and here, we provide a detailed analysis of the inhibition of AChE by CPT-11 and by structural analogs. These studies demonstrate that the terminal dipiperidino moiety in CPT-11 plays a major role in enzyme inhibition, and this has been confirmed by X-ray crystallographic studies of a complex of the drug with Torpedo californica AChE. Our results indicate that CPT-11 binds within the active site gorge of the protein in a fashion similar to that observed with the Alzheimer drug donepezil. The 3D structure of the CPT-11/AChE complex also permits modeling of CPT-11 complexed with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug to the active metabolite. Overall, the results presented here clarify the mechanism of AChE inhibition by CPT-11 and detail the interaction of the drug with the protein. These studies may allow the design of both novel camptothecin analogs that would not inhibit AChE and new AChE inhibitors derived from the camptothecin scaffold.
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PMID:The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action. 1577 91

For the last 15 yr, a great deal of knowledge has been accumulated on health beneficial factors, protein and nonprotein, of bovine milk fat globule membrane (MFGM). Among the health-beneficial components of the MFGM are cholesterolemia-lowering factor, inhibitors of cancer cell growth, vitamin binders, inhibitor of Helicobacter pylori, inhibitor of beta-glucuronidase of the intestinal Escherichia coli, xanthine oxidase as a bactericidal agent, butyrophilin as a possible suppressor of multiple sclerosis, and phospholipids as agents against colon cancer, gastrointestinal pathogens, Alzheimer's disease, depression, and stress. All of the above compel us to consider bovine MFGM as a potential nutraceutical.
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PMID:Invited review: Bovine milk fat globule membrane as a potential nutraceutical. 1595 91

The introduction of celecoxib (Celebrex, Figure 1; GD Searle and Co) as the first cyclooxygenase (COX)2 selective inhibitor in the US and the expected introduction of rofecoxib (Vioxx; Merck and Co Inc) as the first COX2 inhibitor with an acute pain indication, has prompted interest in this class of drugs as a possible therapeutic improvement on dual COX1/COX2 inhibitor NSAIDs, currently on the market. Recognition that the COX-2 enzyme may have a broader role than pain and inflammation has led to studies investigating the efficacy of COX-2 inhibitors for Alzheimer's disease (AD), stroke, cardiovascular disease and colon cancer. Speakers at the second annual conference sponsored by IBC, addressed issues ranging from the basic concepts of COX2 specificity versus selectivity, pathways and regulatory factors related to COX2 expression, the principles underlying the possible broad implications of the COX2 mechanisms, as well as summaries of recently completed clinical trials supporting the clinical efficacy and safety of COX2 inhibitors in humans. The timeliness of this meeting is emphasized by the recent approval of rofecoxib by the FDA Arthritis Advisory panel and the initial reports in the media of toxicity attributed to celecoxib. Preclinical and limited clinical data presented suggest possible therapeutic roles for selective COX2 inhibitors in neurodegeneration due to both AD and stroke, the prevention and treatment of colon cancer, prevention of premature labor, as well as pain and inflammation.
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PMID:COX-2 inhibitors--IBC conference. 12-13 April 1999, Coronado, CA, USA. 1612 36

The anticancer prodrug CPT-11 is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. The 2.6 angstroms resolution crystal structure of its complex with Torpedo californica acetylcholinesterase (TcAChE) demonstrates that CPT-11 binds to TcAChE and spans its gorge similarly to the Alzheimer drug, Aricept. The crystal structure clearly reveals the interactions, which contribute to the inhibitory action of CPT-11. Modeling of the complexes of CPT-11 with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug, shows how binding to either of the two enzymes yields a productive substrate-enzyme complex.
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PMID:The 3D structure of the anticancer prodrug CPT-11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase. 1628

The lysosomal aspartyl protease, cathepsin D, has been suggested to play a role in the metastatic potential of several types of cancer. Cathepsin D is secreted by malignant cells, and is believed to be involved in the breakdown of the extracellular matrix. High levels of active cathepsin D have been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. Also cathepsin D has recently been associated with the development of Alzheimer's disease. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. In the present study twenty-eight compounds containing (hydroxyethyl)amine isosteres with cyclic tertiary amines have been synthesized. These compounds show significant activity as cathepsin D inhibitors, many with IC(50) values in the nanomolar range. For example, the compounds that contain hydroxyethylamines where the amine is formed from N-piperazine-2-carboxylic acid methyl ester, 4y-bb, show IC(50) values ranging from 2.5 to 15 nM.
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PMID:New cathepsin d inhibitors with hydroxyethylamine isosteres: preparation and characterization. 1678 53

This review considers the recent literature in which animal models were used to investigate the purported health benefits of soy isoflavones. The main conclusions are that our animal models demonstrate minimal effects in breast, prostate, and colon cancer prevention, and that, while some cancers may respond to isoflavones, it would appear that isoflavones do not prevent further development once cancer has become established. Regarding cardiovascular health, the lipid-lowering effects of isoflavones have been established, but their efficacy may be less than original research purported. However, it may be considered a bonus of habitual soy consumption that blood cholesterol levels would be reduced somewhat. With respect to osteoporosis and menopausal symptoms, animal models do not show any consistent benefit of isoflavones in preventing osteoporosis, and calcium fortification or the use of prescribed medications are likely much better approaches to combat bone loss. However, our animal models of osteoporosis and menopausal symptoms may not be entirely representative of the human situation. Perhaps the benefit of isoflavones in cognitive skills and in delaying Alzheimer's disease is an area where they can be of some advantage. However, this field is very recent and requires much more research in both humans and animal models before any definitive benefit can be propounded. On the other hand, isoflavones in moderation are probably not dangerous, as few studies have indicated adverse effects. However, large doses have been shown to increase apoptosis and cell degeneration, and in some cancer regimes, once the cancer has progressed beyond the hormone-dependent stage, high doses of isoflavones may be contraindicated. The prospect of mega-dosing from isoflavone supplements opens a new chapter in the risk assessment of isoflavone consumption.
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PMID:A review of the animal models used to investigate the health benefits of soy isoflavones. 1691 38

Non-steroidal anti-inflammatory drugs are widely used for the treatment of pain and inflammation by inhibiting the formation of prostaglandins. However, their use is limited by their side-effects, including gastrointestinal, renal function, cardiovascular and platelet function. Cyclooxygenase activity is the principal target for the action of non-steroidal anti-inflammatory drugs. Two isoforms of cyclooxygenase have been characterized: (i) cyclooxygenase-1, which is found in many tissues and is generally constitutively expressed and synthesizes prostanoids that mediate homeostatic functions; and (ii) cyclooxygenase-2, the inducible isoform, which is mainly expressed at sites of injury or inflammation and synthesizes prostanoids that mediate inflammation, pain and fever. These findings led to the development of selective cyclooxygenase-2 inhibitors, with comparable anti-inflammatory and analgesic properties to traditional non-steroidal anti-inflammatory drugs, but with significantly fewer side-effects. However, these new selective cyclooxygenase-2 inhibitors are not risk free, and care should be taken when using these drugs, especially with elderly patients with multiple medical problems. Finally, the future is bright for the broader usage of these agents in the treatment of diseases other than inflammation and pain, such as Alzheimer's disease, colonic polyp and colon cancer, just to name a few.
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PMID:Cyclooxygenase-2 and antagonists in pain management. 1701 41

Obesity and its related diseases are the leading cause of death in western society, with associated risks of hypertension, coronary heart disease, stroke, diabetes, and breast, prostate and colon cancer. Recent epidemiologic data indicate an increased risk of Alzheimer's disease in association with adult obesity. There is now convincing evidence that, in both human and animal models, the in utero environment may impact on fetal developmental processes, altering offspring homeostatic regulatory mechanisms. "Gestational programming" may result in altered cell number, organ structure, hormonal set points or gene expression, with effects being permanent or expressed only at select offspring ages (e.g., newborn, adult). Our laboratory and others have demonstrated that low birth weight rats, induced by maternal food restriction or uterine artery ligation, paradoxically develop adult obesity with glucose intolerance and hypertension. Recent studies indicate alterations in peripheral (hepatic) and central (hippocampus) IGF-1 gene expression and epigenetic regulation among these offspring. These findings suggest that potential risk factors for the development of Alzheimer's disease may be present as early as newborn life.
Curr Alzheimer Res 2007 Apr
PMID:Gestational programming of offspring obesity: a potential contributor to Alzheimer's disease. 1743 Feb 49

Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".
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PMID:Curcumin as "Curecumin": from kitchen to clinic. 1790 May 36

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.
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PMID:Curcumin: from ancient medicine to current clinical trials. 1832 53


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