The influence of gamma radiation on arachidonic acid release and prostacyclin synthesis

Hahn, G.L.; Menconi, Michael J.; Cahill, M; Polgár, Péter

doi:10.1016/0090-6980(83)90003-5

Cited by 48 publications

(10 citation statements)

References 12 publications

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“…Indeed, the probable mechanism of arachidonic acid release following irradiation is phospholipase A2-mediated hydrolysis of oxidized membrane lipids. In support of this hypothesis, whole body irradiation of animal models results in increased arachidonic acid metabolites (43,44) (reviewed in ref. 45).…”

Section: Discussionmentioning

confidence: 79%

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

Hallahan

Virudachalam

Kuchibhotla

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as Ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a sgnlIng pathway involving the activation of phospholipase A2 and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor a gene. Treatment of human cells with ionizing radiation or H202 was associated with the production of arachidonic acid. Inhibition of phospholipase A2 abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor a gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A2 inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor a production.Signaling pathways activated by DNA (4,5). The complexity ofthis signaling pathway is demonstrated by the number of genes involved in sensing DNA damage and transmitting the signal (5). DNA damage is presumed to be the initiating event in mammalian cell induction of stress response genes following x-ray or UV exposure (6, 7). However, the mechanisms of DNA damage recognition have not been identified in mammalian cells.Signal transduction pathways activated by ionizing radiation include increased phosphotransferase activity of cytoplasmic protein kinases (8-10). Moreover, inhibition of protein kinases blocks radiation-mediated gene induction and effects diverse biological endpoints such as apoptosis (10), radiation survival (11), and induction of the cytokine tumor necrosis factor a (TNF-a) (9). The calcium/phospholipiddependent protein kinase (protein kinase C; PKC) is activated within 15 sec of ionizing radiation exposure and is extinguished by 90 sec in human leukemia HL-60 cells (9). Second messengers that participate in PKC activation following exposure to external stimuli include free fatty acids such as arachidonic acid (12) (16,17). To determine whether arachadonic acid production was associated with radiationmediated signal transduction, we quantified arachidonic acid production in irradiated HL-60 cells and found an increase in arachidonate within 30 min following irradiation.Since phospholipase A2 hydrolyzes phosphatidylcholine to arachidonic acid, we studied the effects of the phospholipase A2 inhibitors mepacrine (18) and bromphenylbromide (BPB) (19). In addition, we studied the effects of dexamethasone and pentoxifylline on radiation-induced fatty acid hydrolysis, as these agents have been shown to inhibit phospholipase A2, reduce the production of cellular mediators of inflammation and tissue injury, and inhibit lipopolysaccharide-induced TNF-a production in monocytes (20, 21). Moreover, glucocorticoids and pentoxifylline are employed clinically to prevent ...

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Section: Discussionmentioning

confidence: 79%

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

Hallahan

Virudachalam

Kuchibhotla

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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“…The level of inflammatory mediators (such as prostaglandins, thromboxanes, and leukotrienes) released under the influence of carrageenan in irradiated rats was higher than that released in non-irradiated ones. The increase in the release of mediators may be attributed to activation of cytoplasmic phospholipase A 2 by ionizing radiation, triggering the release of arachidonic acid from membrane phospholipids and subsequent production of eicosanoids through the cyclooxygenase and lipoxygenase pathways (Hahn et al 1983;Milas and Hanson 1995;Choy and Milas 2003). The level of PGE 2 and LTB 4 increased nearly by 80% in the fluid exudates of the air pouch of the carrageenan-treated irradiated rats as compared to non-irradiated ones.…”

Section: Discussionmentioning

confidence: 92%

“…Since the early 1980s it has been known that inhibiting the production of PGs leads to potentiation of the radiation response in irradiated tissues (Hahn et al 1983). However, since the discovery of the inducible form of cyclooxygenase (COX-2), it became apparent that it is this enzyme Fig.…”

Section: Discussionmentioning

confidence: 99%

The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats

et al. 2009

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The potential value of selective and non-selective COX-2 inhibitors in preventing some of the biochemical changes induced by ionizing radiation was studied in rats exposed to carrageenan-induced paw edema and 6-day-old air pouch models. The animals were exposed to different exposure levels of gamma-radiation, namely either to single doses of 2 and 7.5 Gy or a fractionated dose level of 7.5 Gy delivered as 0.5 Gy twice weekly for 7.5 weeks. The inflammatory response produced by carrageenan in irradiated rats was markedly higher than that induced in non-irradiated animals, and depended on the extent of irradiation. Celecoxib, a selective COX-2 inhibitor, in doses of 3, 5, 10, and 15 mg/kg was effective in reducing paw edema in irradiated and non-irradiated rats in a dose-dependent manner as well as diclofenac (3 mg/kg), a non-selective COX inhibitor. Irradiation of animals before the induction of the air pouch by an acute dose of 2 Gy led to a significant increase in leukocytic count, as well as in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), LTB(4), PGE(2) (as an index of COX-2 activity), TXB(2) (as an index of COX-1 activity), and the plasma level of MDA. This increase in level of these parameters was more marked than that observed in the non-irradiated animals subjected to the inflammagen. The blood GSH level was not affected by the dose of irradiation used, whereas superoxide dismutase (SOD) activity was suppressed. In many respects, celecoxib (5 mg/kg) was as potent as diclofenac in decreasing the elevated levels of IL-6, IL-1beta, TNF-alpha, LTB(4), PGE(2), but lacked any significant effect on TXB(2) level. Since it is mostly selective for COX-2 with a rare effect on COX-1 enzyme, both drugs at the selected dose levels showed no effect on level of MDA, GSH, and SOD activity.

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“…[1][2][3][4][5][6][7][8][9][10] It has long been suggested that prostaglandins, the products of cyclooxygenase (COX) enzyme activity on arachidonic acid, play a role in cell survival after ionizing radiation. The addition of prostaglandins or their analogs has been shown to be radioprotective in a number of cell types, [11][12][13][14] whereas others have suggested that prostaglandins have differential effects depending on the cell type.…”

Section: Prostaglandins As Radioprotective Agentsmentioning

confidence: 99%

COX-2 Inhibitors as Radiosensitizing Agents for Cancer Therapy

Davis¹,

Hunter²,

Trifan³

et al. 2003

American Journal of Clinical Oncology

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Prostaglandins have long been known to impact the radiosensitivity of cells and tissues, and many studies have centered on exploiting nonspecific prostaglandin inhibitors such as NSAIDs for therapeutic gain. These studies have ultimately been unsuccessful due to the lack of targeted specificity against the tumor. The discovery of the inducible cyclooxygenase enzyme (COX-2) and development of some highly selective inhibitors (which spare the constitutive COX-1 activity) has renewed excitement for modulating tumor prostaglandins as a method of specific radiosensitization of tumors, while sparing normal tissues. This review discusses these new data and generates a rationale for use of COX-2 inhibitors as radiosensitizing agents in cancer therapy.

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The influence of gamma radiation on arachidonic acid release and prostacyclin synthesis

Cited by 48 publications

References 12 publications

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats

COX-2 Inhibitors as Radiosensitizing Agents for Cancer Therapy

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