Biphasic effects of cyclosporin A on formyl‐methionyl‐leucyl‐phenylalanine stimulated responses in HL‐60 cells differentiated into neutrophils

Nguyen, Nathalie S D; Pulido, Silvia; Rüegg, Urs T.

doi:10.1038/sj.bjp.0702020

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…Several studies have reported the elevation of ROS in response to 4-HPR in various cell types (Sun et al, 1999) and in this context, we have already proposed a mediatory role for oxidative stress during 4-HPR action on ceramide production and cell survival in the present study; on the other hand, PSC 833 has been reported to suppress the generation of ROS (Nguyen et al, 1998). A role for ceramide has been recently implicated during nitric oxide-induced cell death (Rabkin, 2002) and 4-HPR is known to induce nitric oxide synthase in breast cancer cells (Simeone et al, 2002).…”

Section: Discussionsupporting

confidence: 73%

Fenretinide stimulates redox-sensitive ceramide production in breast cancer cells: potential role in drug-induced cytotoxicity

2004

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The synthetic retinoid N-(4-hydroxphenyl) retinamide (4HPR) has manifold actions, which may contribute to its chemopreventive effects on breast cancer cell growth and progression. A role for ceramide as a stress-response signal is investigated here during the cytotoxic action of 4HPR in MCF-7 cells. N-(4-hydroxphenyl) retinamide induced a dose-dependent decline in cell growth and survival associated with a maximal 10-fold increase in ceramide production at 10 mM. N-(4-hydroxphenyl) retinamide exhibited a greater potency than all-trans retinoic acid (ATRA) on growth inhibition and ceramide production. The synthetic peroxisome proliferator-activated receptors agonist troglitazone (TGZ), but not the native ligand 15-deoxy-delta 12,14-prostaglandin J 2 , abrogated both these actions of 4HPR but not that of ATRA. The antioxidant N-acetylcysteine mimicked the abrogative effect of TGZ on 4HPR action, while the exogenous oxidant H 2 O 2 also stimulated ceramide production. The inhibitors of de novo ceramide synthesis, fumonisin B 1 and myriocin, blocked the ceramide response to 4HPR and partially reversed the apoptotic response, but did not prevent the overall decline in cell survival. The pancaspase inhibitor Z-VAD fmk reduced the decrease in cell survival caused by 4HPR, but did not affect the ceramide response. These findings describe a novel redox-sensitive elevation of ceramide levels associated with the cytotoxic response of breast cancer cells to 4HPR. However, a major mediatory role for this sphingolipid in this context remains equivocal.

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Section: Discussionsupporting

confidence: 73%

Fenretinide stimulates redox-sensitive ceramide production in breast cancer cells: potential role in drug-induced cytotoxicity

2004

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“…Conceivably, oxidative stress in grafts given to carriers of the T allelic variants could have been amplified by ROS generated and released in increased amounts by infiltrating lymphocytes, polymorphonuclear cells, and other host leukocytes. [11][12][13] This effect might be sustained by increased intracellular CsA concentration secondary to depressed CsA efflux via P-glycoprotein transport in this population. 9,10 Although this is consistent with findings that both acute and chronic CsA nephrotoxicity are associated with oxidative stress and can be limited by free radical scavengers acting to block ROS, [25][26] ad hoc studies using mass spectrometry technology to measure intracellular CsA concentration are needed to specifically address this working hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, CsA blood levels increased, decreased, or did not change in different settings, likely because of different balances between enhanced distribution into the tissue compartment and decreased excretion into the gastrointestinal lumen or urinary tract. 7 Increased CsA concentrations in lymphocytes, 11 polymorphonuclear cells, 12 and other circulating leukocytes 13 have been associated with increased production and release of reactive oxygen species (ROS). ROS production by leukocytes is the primary de- fense against invading micro-organisms, but has also been involved in the pathogenesis of ischemia-reperfusion damage of engrafted tissues or organs.…”

mentioning

confidence: 99%

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Cattaneo

Ruggenenti

Baldelli

et al. 2009

Journal of the American Society of Nephrology

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Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8-and 3.5-fold higher risk for DGF, respectively (P ϭ 0.022 and P ϭ 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes. The introduction of cyclosporine A (CsA) therapy in the early 1980s opened a new era in organ transplantation. Compared with steroid-and azathioprine-based regimens, immunosuppressive protocols including this inhibitor of calcineurin-a key enzyme involved in T cell activation 1 -decreased the incidence of acute rejections from 40% to 50% to 20% to 30% and increased one-year survival rates of the grafts from 60% to between 80% and 90%. 2 Thirty years later, CsA remains a cornerstone of immunosuppressive therapy for recipients of both renal and nonrenal transplants worldwide. However, standard recommended doses are associ-

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“…Both proteins, Rac2 and PKC, are constituents of the machinery responsible for the activation of NADPH oxidase (Kwong et al 1993, Bokoch & Knaus 1994 and are thus amenable to participate in Ang II-dependent signal transduction pathways. Also, it has been reported that the rapid CsAinduced depression of the respiratory burst in neutrophils stimulated by fMLP is due to a primary reduction of Ca 2C signalling (Nguyen et al 1998). In this context, present observations illustrate for the first time the prevention of Ang II-dependent intracellular Ca 2C elevation through Rac2 inhibition (by C. difficile toxin A), with simultaneous decrease of CaN activity, events which are consistent with the view that Rac2 activation is coupled to the elicitation of intracellular oxidative stress by Ang II in human neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils

Bekay

Álba²,

Reyes³

et al. 2007

Journal of Molecular Endocrinology

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Angiotensin II (Ang II) highly stimulates superoxide anion production by neutrophils. The G-protein Rac2 modulates the activity of NADPH oxidase in response to various stimuli. Here, we describe that Ang II induced both Rac2 translocation from the cytosol to the plasma membrane and Rac2 GTP-binding activity. Furthermore, Clostridium difficile toxin A, an inhibitor of the Rho-GTPases family Rho, Rac and Cdc42, prevented Ang II-elicited O K 2 =ROS production, phosphorylation of the mitogen-activated protein kinases (MAPKs) p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun Nterminal kinase 1/2, and Rac2 activation. Rac2 GTPase inhibition by C. difficile toxin A was accompanied by a robust reduction of the cytosolic Ca 2C elevation induced by Ang II in human neutrophils. Furthermore, SB203580 and PD098059 act as inhibitors of p38MAPK and ERK1/2 respectively, wortmannin, an inhibitor of phosphatidylinositol-3-kinase, and cyclosporin A, a calcineurin inhibitor, hindered both translocation of Rac2 from the cytosol to the plasma membrane and enhancement of Rac2 GTP-binding elicited by Ang II. These results provide evidence that the activation of Rac2 by Ang II is exerted through multiple signalling pathways, involving Ca 2C /calcineurin and protein kinases, the elucidation of which should be insightful in the design of new therapies aimed at reversing the inflammation of vessel walls found in a number of cardiovascular diseases.

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Biphasic effects of cyclosporin A on formyl‐methionyl‐leucyl‐phenylalanine stimulated responses in HL‐60 cells differentiated into neutrophils

Cited by 7 publications

References 27 publications

Fenretinide stimulates redox-sensitive ceramide production in breast cancer cells: potential role in drug-induced cytotoxicity

Fenretinide stimulates redox-sensitive ceramide production in breast cancer cells: potential role in drug-induced cytotoxicity

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils

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