Therapeutic options for 5-lipoxygenase inhibitors

Werz, Oliver; Steinhilber, Dieter

doi:10.1016/j.pharmthera.2006.05.009

Cited by 236 publications

(215 citation statements)

References 196 publications

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“…However, because of the different experimental settings applied for analysis of the interference of garcinol with these targets, direct comparison of garcinol´s potencies is difficult. 5-LO and mPGES-1 are crucial enzymes in the biosynthesis of key mediators in inflammatory processes [16,19], providing a rationale for the anti-inflammatory effects of garcinol. Moreover, 5-LO and mPGES-1 are overexpressed in many tumors, and PGE 2 as well as 5-LO products play important roles in tumorigenesis [16,18,19].…”

Section: Discussionmentioning

confidence: 99%

“…5-LO and mPGES-1 are crucial enzymes in the biosynthesis of key mediators in inflammatory processes [16,19], providing a rationale for the anti-inflammatory effects of garcinol. Moreover, 5-LO and mPGES-1 are overexpressed in many tumors, and PGE 2 as well as 5-LO products play important roles in tumorigenesis [16,18,19]. Together, we conclude that the interference of garcinol with 5-LO and mPGES-1 provides a molecular basis for its documented anti-carcinogenic and antiinflammatory properties.…”

Section: Discussionmentioning

confidence: 99%

“…But also tumorigenesis, particularly of colon, breast, prostate, and lung carcinoma has been associated with excessive PGE 2 and LT formation [16,18,19]. COX-2 selective inhibitors have shown a chemopreventive potential [41], and mPGES-1 is overexpressed in various cancers such as non-small cell lung cancer, invasive breast cancer, colorectal cancer, and gastric cancer [19].…”

Section: Page 21 Of 39mentioning

confidence: 99%

“…COX-2 and/or 5-LO are also overexpressed in various cancer cells (e.g., prostate, breast, lung, and colon) [14][15][16], and pre-clinical studies indicate tumor-preventive effects of COX inhibition by non steroidal antiinflammatory drugs (NSAIDs) [17]. Moreover, pharmacological suppression of the 5-LO pathway, using 5-LO inhibitors or inhibitors of the 5-LO-activating protein (FLAP), causes 6…”

Section: Introductionmentioning

confidence: 99%

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Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Koeberle

Northoff

Werz

2009

Biochemical Pharmacology

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To cite this version:Andreas Koeberle, Hinnak Northoff, Oliver Werz. Identification of 5-lipoxygenase and microsomal prostaglandin E synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol. Biochemical Pharmacology, Elsevier, 2009, 77 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Ca 2+ -ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF 1α , or isolated human recombinant COX-2 were significantly affected by garcinol (≤ 30 µM). Together, the high potency of garcinol to selectively suppress PGE 2 synthesis and 5-lipoxygenase product formation provides a molecular basis for the anti-inflammatory and anti-carcinogenic effects of garcinol and rationalizes its therapeutic use.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Page 21 Of 39mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Koeberle

Northoff

Werz

2009

Biochemical Pharmacology

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“…Our workflow comprises the search for common substructures of known ligands for each target followed by the identification of multitarget relevant substructures among the target-specific substructures. We used our multiSOM approach to retrieve molecular fragments, which target 5-lipoxygenase (5-LO) 11 and soluble epoxide hydrolase (sEH). 12,13 We validated these findings by saturation transfer difference (STD)-NMR 14,15 and functional in vitro assay systems.…”

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confidence: 99%

Exploring the Chemical Space of Multitarget Ligands Using Aligned Self-Organizing Maps

Achenbach

Klingler

Blöcher

et al. 2013

ACS Med. Chem. Lett.

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Design of multitarget drugs and polypharmacological compounds has become popular during the past decade. However, the main approach to design such compounds is to link two selective ligands via a flexible linker. Although such chimeric ligands often have reasonable potency in vitro, the in vivo efficacy is low due to high molecular weight, low ligand efficiency, and poor pharmacokinetic profile. We developed an unprecedented in silico approach for fragment-based design of multitarget ligands. It relies on superposition of the chemical spaces related to the affinity on single targets represented by selforganizing maps. We used this approach for screening of molecular fragments, which bind to the enzymes 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH). Using STD-NMR and activity-based assays, we were able to identify fragments binding to both targets. Furthermore, we were able to expand one of the fragments to a potent dual inhibitor bearing a reasonable molecular weight (MW = 446) and high affinity to both targets (IC 50 of 0.03 μM toward 5-LO and 0.17 μM toward sEH).

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Reactive Oxygen Species

2012

Oxidation of Amino Acids, Peptides, and Proteins

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Reactive oxygen species (ROS) are generated in mammalian cells via both enzymatic and non-enzymatic mechanisms. Although certain ROS production pathways are required for the performance of specific physiological functions, excessive ROS generation is harmful, and has been implicated in the pathogenesis of a number of diseases. Among the ROS-producing enzymes, NADPH oxidase is widely distributed among mammalian cells, and is a crucial source of ROS for physiological and pathological processes. Reactive oxygen species are also generated by arachidonic acid (AA) metabolites, which are released from membrane phospholipids via the activity of cytosolic phospholipase A2 (cPLA2). In this study, we describe recent studies concerning the generation of ROS by AA metabolites. In particular, we have focused on the manner in which AA metabolism via lipoxygenase (LOX) and LOX metabolites contributes to ROS generation. By elucidating the signaling mechanisms that link LOX and LOX metabolites to ROS, we hope to shed light on the variety of physiological and pathological mechanisms associated with LOX metabolism. [BMB reports 2008; 41(8): 555-559]Reactive oxygen species (ROS) are highly reactive O2 metabolites, such as superoxide radicals (O2 •−

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Therapeutic options for 5-lipoxygenase inhibitors

Cited by 236 publications

References 196 publications

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Exploring the Chemical Space of Multitarget Ligands Using Aligned Self-Organizing Maps

Reactive Oxygen Species

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