Platelet-activating factor and its methoxy-analogue et-18-OCH3 stimulate immediate early gene expression in rat astroglial cultures

Albani, P. Dell'; Condorelli, D. F.; Mudó, G.; Amico, Carla; Bindoni, M; Belluardo, Natale

doi:10.1016/0197-0186(93)90031-y

Cited by 27 publications

(5 citation statements)

References 33 publications

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“…The weak induction of c-fos by ET-18-OCH 3 [47,178,188] was not related to the induction of apoptosis, as antisense oligonucleotides against c-fos did not prevent ET-18-OCH 3 -induced apoptosis [47]. This is in agreement with the evidence from c-Fos-deficient mice demonstrating that c-fos is not essential for the induction of apoptosis [189].…”

Section: Et-18-och 3 Affects Gene Expressionsupporting

confidence: 80%

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

Mollinedo¹,

Gajate²,

Martín‐Santamaría³

et al. 2004

CMC

123

103

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Synthetic ether-linked analogues of phosphatidylcholine and lysophosphatidylcholine, collectively named as antitumour lipids (ATLs), were initially synthesized in the late 60s, but have attracted a renewed interest since the finding that the ether lipid 1-O -octadecyl-2-O -methyl-rac-glycero-3-phosphocholine (ET-18-OCH 3 , edelfosine), a synthetic analogue of 2-lysophosphatidylcholine considered the ATL prototype, induces a selective apoptotic response in tumour cells, sparing normal cells. Unlike most chemotherapeutic agents currently used, ET-18-OCH 3 does not interact with DNA, but act at the cell membrane, and thereby its effects seem to be independent of the proliferative state of target cells. Each part of the molecular structure of ET-18-OCH 3 is important for its optimal proapoptotic activity. Recent progress has unveiled the molecular mechanism underlying the apoptotic action of ET-18-OCH 3 , involving membrane rafts and Fas/CD95 death receptor, and has led to the proposal of a two-step model for the ET-18-OCH 3 selective action on cancer cells, namely: a) ET-18-OCH 3 uptake into the tumour cell, but not in normal cells; b) intracellular activation of Fas/CD95 through its translocation and capping into membrane rafts. ET-18-OCH 3 constitutes the first antitumour drug acting through the intracellular activation of the Fas/CD95 death receptor. Computational docking studies have allowed us to propose a molecular model for the putative interaction of ET-18-OCH 3 with the intracellular Fas/CD95 death domain. This novel mechanism of action represents a new way to target tumour cells in cancer chemotherapy and can be of interest as a new framework in designing novel and more selective proapoptotic antitumour drugs.

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Section: Et-18-och 3 Affects Gene Expressionsupporting

confidence: 80%

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

Mollinedo¹,

Gajate²,

Martín‐Santamaría³

et al. 2004

CMC

123

103

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“…ET-18-OCH 3 is reported to be a membrane interactive drug, selectively cytotoxic toward neoplastic cells in an apoptotic fashion [2,4,21] and it has also been shown to be an eective cytostatic agent at no toxic concentration [10]. Moreover, ET-18-OCH 3 shows functional activities in normal cells and particularly, in in vitro rat astrocytes, in which it stimulates NO biosynthesis more than LPS, activates early gene expression and elicits protective reactions increasing glutamine synthetase activity and HSP70 levels at low doses (1±4 mg/ml) [7,14,27]. Antitumor and apoptotic activity of ET-18-OCH 3 seems to be associated with disturbance of the phospholipid metabolism in the plasmatic membrane with subsequent increase of intra-cellular free calcium and/or modi®cation of Ptd Ins phospholipase C and protein kinase C activities as well as with the activation of some proto-oncogenes [4,11,14,16].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it has been demonstrated that ET-18-OCH 3 promotes functional activities in normal cells, too. In fact, the drug modu-lates interleukin-1 and -2 secretion by lymphocytes, increases intrathymic cell trac, stimulates the biosynthesis of interleukin-6 in human thymic epithelial cells [3,6,8,13], and induces``immediate early genes'' expression and the biosynthesis of nitric oxide (NO) in rat astrocytes [7,14]. In addition, as regards these latter cell types, we have demonstrated that the drug, at low doses, stimulates cellular maturation and protective responses, whereas at high doses it is cytotoxic and induces the release of low molecular weight DNA and loss of cell viability.…”

Section: Introductionmentioning

confidence: 99%

ET‐18‐OCH₃‐induced cytotoxicity and DNA damage in rat astrocytes

Renis

Cardile

Palumbo

et al. 2000

Intl J of Devlp Neuroscience

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The ether lipid 1-octadecyl-2-methyl-rac-glicero-3-phosphocholine (ET-18-OCH(3)) is known to be selectively cytotoxic toward several types of tumor cells, in which it seems to activate a process of apoptotic cell death. Moreover, the drug has been demonstrated to be active in normal cells too, particularly in rat astrocytes. In these cells at low dosage (from 1 to 6 microg/ml of medium) ET-18-OCH(3) stimulates maturation and protective responses, whereas at increasing dosages (from 8 to 20 microg/ml) it shows cytotoxic effects. The present study demonstrates that when ET-18-OCH(3) is added to astrocytes, it activates, in a time- and concentration-dependent manner, an oxidative process by increasing both the generation of reactive oxygen species (ROS), including nitric oxide, and lipid peroxidation. When there is a high ET-18-OCH(3) concentration or the time of treatment is prolonged, the increased oxidative condition seems to trigger DNA fragmentation (monitored by COMET assay) as well as loss in cell viability. These cytotoxic effects indicate that ROS may be considered, in our experimental model, as executioners of a program of cell death. In addition, ET-18-OCH(3) being a promising molecule in antitumor therapy, our data, while reinforcing the importance of monitoring the therapeutic drug dosage employed, also suggest that it may be useful to associate some antioxidants with antitumor treatments.

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“…Another intermediate product of PLA 2 is platelet activating factor (PAF), which together with PLA 2, increases TNF-~ secretion (Lazarewicz, 1992;Wcis~o and Szczyklik, 1997). PAF has been shown to increase the expression of early-response genes in cultured astrocytes (Dell'Albani et al, 1993). Ca 2+ alone also increases the expression of early-response genes,…”

Section: Calciummentioning

confidence: 99%

Role of astrocytes in pathogenesis of ischemic brain injury

Gabryel

Trzeciak

2001

neurotox res

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Astrocytes play an important role in the homeostasis of the CNS both in normal conditions and after ischemic injury. The swelling of astrocytes is observed during and several seconds after brain ischemia. Then ischemia stimulates sequential morphological and biochemical changes in glia and induces its proliferation. Reactive astrocytes demonstrate stellate morphology, increased glial fibrillary acidic protein (GFAP) immunoreactivity, increased number of mitochondria as well as elevated enzymatic and non-enzymatic antioxidant activities. Astrocytes can re-uptake and metabolize glutamate and in this way they control its extracellular concentration. The ability of astrocytes to protect neurons against the toxic action of free radicals depends on their specific energy metabolism, high glutathione level, increased antioxidant enzyme activity (catalase, superoxide dismutase, glutathione peroxidase) and overexpression of antiapoptotic bcl-2 gene. Astrocytes produce cytokines (TNF-alpha, IL-1, IL-6) involved in the initiation and maintaining of immunological response in the CNS. In astrocytes, like in neurones, ischemia induces the expression of immediate early genes: c-fos, c-jun, fos B, jun B, jun D, Krox-24, NGFI-B and others. The protein products of these genes modulate the expression of different proteins, both destructive ones and those involved in the neuroprotective processes.

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Platelet-activating factor and its methoxy-analogue et-18-OCH3 stimulate immediate early gene expression in rat astroglial cultures

Cited by 27 publications

References 33 publications

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

ET‐18‐OCH₃‐induced cytotoxicity and DNA damage in rat astrocytes

Role of astrocytes in pathogenesis of ischemic brain injury

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Platelet-activating factor and its methoxy-analogue et-18-OCH3 stimulate immediate early gene expression in rat astroglial cultures

Cited by 27 publications

References 33 publications

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

ET‐18‐OCH3‐induced cytotoxicity and DNA damage in rat astrocytes

Role of astrocytes in pathogenesis of ischemic brain injury

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ET‐18‐OCH₃‐induced cytotoxicity and DNA damage in rat astrocytes