Neutrophils biosynthesize leukotoxin, 9, 10-epoxy-12-octadecenoate

Hayakawa, Mika; Sugiyama, Satoru; Takamura, Tadanobu; Yokoo, Kazuhisa; Iwata, Masaru; Suzuki, Kiyoshi; Taki, Fumio; Takahashi, Shigetoshi; Ozawa, Takayuki

doi:10.1016/0006-291x(86)91227-1

Cited by 83 publications

(33 citation statements)

References 7 publications

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“…The results indicate the highest enrichment with 6-hour DSF treatment and 12,13-EODE (Supplementary Table S3). This compound, 12,13-cis epoxide of linoleic acid is generated by neutrophils during the oxidative burst (27). Also irinotecan, a topoisomerase 1 inhibitor was among the most enriched drugs when compared with 6-hour DSF treatment.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Iljin

Ketola

Vainio

et al. 2009

Clinical Cancer Research

200

165

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Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically explore most currently marketed drugs and drug-like molecules for their efficacy against a panel of prostate cancer cells. Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910 drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). The EC 50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration. Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations. DSF reduced tumor growth in vivo, induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF was potentiated by copper in vitro. Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically wellknown molecules can be readily translated to in vivo preclinical studies and clinical trials. (Clin Cancer Res 2009;15(19):6070-8)

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Section: Resultsmentioning

confidence: 99%

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Iljin

Ketola

Vainio

et al. 2009

Clinical Cancer Research

200

165

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“…In our incubations with AM we have not been able to detect any of these metabolites. Another interesting class of linoleic acid metabolites is produced by neutrophils and can also be found in rat lung lavage fluid after pure oxygen breathing [23,24], an experimental model to study inflammatory processes in the lungs. These epoxide derivatives, named leukotoxins, show a typical uncoupling effect on mitochondrial respiration and relax rat stomach smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase‐catalyzed formation of 9‐hydroxylinoleic acid by guinea pig alveolar macrophages under non‐stimulated conditions

1986

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Data are presented on the formation of a linoleic acid oxygenation product under basal conditions by guinea pig alveolar macrophages (AM). Under non-stimulated conditions 20 x lo6 AM released about 1 nmol 9-hydroxylinoleic acid (9-HODE) during a 15 min incubation. Furthermore, AM released more than 2 nmol 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT), a byproduct of the formation of thromboxane A, 9-HODE and HHT were the most prominent products formed under the incubation conditions used. These products were formed via a cyclooxygenase-catalyzed reaction, since their formation was inhibited by 1 PM indomethacin. Thus, under basal conditions AM possess substantial cyclooxygenase activity. The biological significance of I)-HODE and related substances is discussed. Alveolar macrophage 9-Hydroxylinoleic acid

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“…[11][12][13] sEH has also been shown to metabolize 9,10-epoxy-12-octadecenoate (called leukotoxin, coronaric acid, or 9,10-EpOME) and 12,13-epoxy-9-octadecenoate (called isoleukotoxin, vernolic acid or 12,13-EpOME), cytochrome p450 metabolites of linoleic acid. [14][15][16] These compounds were identified as having a role in the development of acute respiratory distress syndrome (ARDS). [17] Several recent studies have explored the signaling in C. elegans.…”

Section: Introductionmentioning

confidence: 99%

Identification of two epoxide hydrolases in Caenorhabditis elegans that metabolize mammalian lipid signaling molecules

Harris

Aronov

Jones

et al. 2008

Archives of Biochemistry and Biophysics

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We have identified two genes in the genomic database for C. elegans that code for proteins with significant sequence similarity to the mammalian soluble epoxide hydrolase (sEH). The respective transcripts were cloned from a mixed stage cDNA library from C. elegans. The corresponding proteins obtained after recombinant expression in insect cells hydrolyzed standard epoxide hydrolase substrates, including epoxyeicosatrienoic acids (EETs) and leukotoxins (EpOMEs). The enzyme activity was inhibited by urea-based compounds originally designed to inhibit the mammalian sEH. In vivo inhibition of the enzymes using the most potent of these compounds resulted in elevated levels of the EpOMEs in the nematode. These results suggest that the hydrolases are involved in the metabolism of possible lipid signaling molecules in C. elegans.

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Neutrophils biosynthesize leukotoxin, 9, 10-epoxy-12-octadecenoate

Cited by 83 publications

References 7 publications

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth

Cyclooxygenase‐catalyzed formation of 9‐hydroxylinoleic acid by guinea pig alveolar macrophages under non‐stimulated conditions

Identification of two epoxide hydrolases in Caenorhabditis elegans that metabolize mammalian lipid signaling molecules

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