Inhibition of alveolar macrophage 5-lipoxygenase metabolism by auranofin

Peters‐Golden, Marc; Shelly, Candace

doi:10.1016/0006-2952(89)90306-7

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…First, resident AM have a substantially greater capacity to synthesize LTB 4 than do macrophages from other anatomic sites (28,42,43). In addition, this molecule is a potent chemoattractant and functional activator of granulocytic cells, including neutrophils and eosinophils (44), and has been shown to account for an appreciable amount of the neutrophil chemotactic activity elaborated by AM (45); LTB 4 synthesized by AMs could therefore play an important direct role in the leukocyte recruitment which characterizes IPF.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Wilborn¹,

Bailie²,

Coffey³

et al. 1996

J. Clin. Invest.

172

140

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Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by inflammation, fibroblast proliferation, and accumulation of extracellular matrix proteins. Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this study, we measured the levels of immunoreactive LTs B 4 and C 4 in homogenates of lung tissue obtained from patients with newly diagnosed, untreated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery for bronchogenic carcinoma. Compared to homogenates of nonfibrotic control lung, homogenates from IPF patients contained 15-fold more LTB 4 and 5-fold more LTC 4 . IPF homogenate levels of LTB 4 were significantly correlated with histologic indices of both inflammation ( r ϭ 0.861) and fibrosis ( r ϭ 0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nuclear membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an "activated" localization pattern was significantly more frequent in IPF lung (19.2 Ϯ 3.3% of cells) than in control lung (9.3 Ϯ 0.9%); this localization pattern was rarely seen (3.2%) in sections from a truly normal transplant donor lung. Consistent with these data, AMs obtained from IPF patients by bronchoalveolar lavage, purified by adherence, and cultured in the absence of a stimulus for 16 h elaborated significantly greater amounts of LTB 4 and LTC 4 than did control AMs obtained from normal volunteers. These data indicate that the 5-LO pathway is constitutively activated in the lungs of patients with IPF, and the AM represents at least one cellular source of LT overproduction in this disorder. We speculate that LTs participate in the pathogenesis of IPF, and their overproduction in this disorder may be amenable to specific pharmacotherapy. (

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Section: Discussionmentioning

confidence: 99%

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Wilborn¹,

Bailie²,

Coffey³

et al. 1996

J. Clin. Invest.

172

140

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“…Release and metabolism of AA was assessed in PMN whose lipids were prelabeled by incubation with [ 3 H]AA (60-100 Ci/mmol sp act) (Dupont-New England Nuclear, Boston, MA) in the medium during culture for 1.5 h. Cells were then centrifuged and washed, and AA metabolism was determined by incubation in Iscove's medium for 30 min with 10 M A23187. To assess total AA release, cells were stimulated with A23187 in the presence of 0.1% BSA and radioactivity in the medium was determined (20). Cell supernatants were extracted using C 18 SepPaks, Waters Corp., Milford, MA, and radiolabeled eicosanoids were separated by reverse-phase HPLC (20), identified by co-elution with authentic standards (Cayman Chemicals, Ann Arbor, MI), and quantitated using an on-line radioactivity detector (Radiomatic model 515; Packard Instruments, Downers Grove, IL).…”

Section: Analysis Of [mentioning

confidence: 99%

“…To assess total AA release, cells were stimulated with A23187 in the presence of 0.1% BSA and radioactivity in the medium was determined (20). Cell supernatants were extracted using C 18 SepPaks, Waters Corp., Milford, MA, and radiolabeled eicosanoids were separated by reverse-phase HPLC (20), identified by co-elution with authentic standards (Cayman Chemicals, Ann Arbor, MI), and quantitated using an on-line radioactivity detector (Radiomatic model 515; Packard Instruments, Downers Grove, IL). Radiolabeled products released were expressed as a percentage of radioactivity incorporated into cellular membrane phospholipids.…”

Section: Analysis Of [mentioning

confidence: 99%

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

Coffey¹,

Phare²,

George³

et al. 1998

J. Clin. Invest.

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Neutrophil (PMN) dysfunction occurs in HIV infection. Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway that play a role in host defense and are synthesized by PMN. We investigated the synthesis of LT by PMN from HIV-infected subjects. There was a reduction (4.0 Ϯ 1.3% of control) in LT synthesis in PMN from HIV-infected compared with normal subjects. This was associated with reduced expression of 5-LO-activating protein (31.2 Ϯ 9.6% of normal), but not of 5-LO itself. Since HIV does not directly infect PMN, we considered that these effects were due to reduced release of cytokines, such as granulocyte colony-stimulating factor (G-CSF). We examined the effect of G-CSF treatment (300 g daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB 4 synthesis was increased on day 4 of G-CSF treatment, and returned toward day 1 levels on day 7. 5-LO and 5-LO-activating protein expression were increased in parallel. As a functional correlate to this increase in PMN LT synthesis by G-CSF, we examined the effects on killing of Cryptococcus neoformans . Anticryptococcal activity of PMN from HIV-infected subjects was less than that of PMN from normal subjects. G-CSF treatment improved fungistatic activity of PMN. This increase in antifungal activity was attenuated by in vitro treatment with the LT synthesis inhibitor, MK-886. In conclusion, PMN from HIV-infected subjects demonstrate reduced 5-LO metabolism and antifungal activity in vitro, which was reversed by in vivo G-CSF therapy. ( J. Clin. Invest. 1998. 102:663-670.)

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“…Auranofin inhibited 5-LO in stimulated neutrophils [60-62] and in stimulated alveolar macrophages [63]. LTB4 is a major pro-inflammatory leukotriene product of arachidonate metabolism by 5-LO.…”

Section: Introductionmentioning

confidence: 99%

“…An early study gave evidence of auranofin's ability to cause arachidonic acid release from macrophages [63]. This was accompanied by some increase in thromboxane and prostaglandin E2, PGE2 [63].…”

Section: Introductionmentioning

confidence: 99%

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Kast¹,

2014

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CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

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Inhibition of alveolar macrophage 5-lipoxygenase metabolism by auranofin

Cited by 10 publications

References 27 publications

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

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