Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (ROS). The aim of this study was to identify mechanisms generating ROS and apoptosis of neuroblastoma cells in response to fenretinide. Fenretinide-induced ROS or apoptosis of SH-SY5Y or HTLA 230 neuroblastoma cells were not blocked by Nitro l-argenine methyl ester (l-NAME), an inhibitor of nitric oxide synthase. Flavoprotein-dependent superoxide-producing enzymes such as NADPH oxidase were also not involved in fenretinide-induced apoptosis or ROS generation. Similarly, ketoconazole, a cytochrome P450 inhibitor, and inhibitors of cyclooxygenase (COX) were also ineffective. In contrast, inhibition of phospholipase A(2) or lipoxygenases (LOX) blocked the induction of ROS and apoptosis in response to fenretinide. Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis. The effects of eicosatriynoic acid, a specific 12-LOX inhibitor, were reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid and 12 (S)-hydroxyeicosatetraenoic acid. The targeting of 12-LOX in neuroblastoma cells may thus be a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.
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PMID:Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma. 1285 36

Neuroblastoma, the most common extracranial solid tumour in children, may undergo spontaneous differentiation or regression, but the majority of metastatic neuroblastomas have poor prognosis despite intensive treatment. Retinoic acid and its analogues regulate growth and differentiation of neuroblastoma cells in vitro, and 13-cis retinoic acid has shown activity against human neuroblastomas in vivo. Fenretinide [N-(4-hydroxyphenyl)retinamide] has been identified as a synthetic retinoid able to induce apoptosis of numerous malignant cell lines in vitro, including neuroblastoma. Furthermore, in animal models, fenretinide has shown chemopreventive and therapeutic efficacy against several malignancies without any obvious signs of toxicity. To investigate the anti-neuroblastoma tumour growth effects of oral fenretinide in vivo we used a human neuroblastoma xenograft model. Nude rats with established neuroblastoma xenograft tumours were treated orally with fenretinide for 10 days. Five different doses of fenretinide were used ranging from 2.5 to 75 mg/rat/day (10-300 mg/kg). Tumour volumes and toxic side effects were monitored during treatment and tumour weights were recorded at autopsy. In this study we found no significant anti-tumour growth effects of fenretinide in vivo, when used as oral treatment of rats with established neuroblastoma xenograft tumours. Furthermore, there were no intra tumoural differences in treated compared to untreated tumours. However, because of the promising results of fenretinide on neuroblastoma growth in vitro, further in vivo studies are warranted using other modalities of drug administration.
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PMID:Evaluation of anti-tumour effects of oral fenretinide (4-HPR) in rats with human neuroblastoma xenografts. 1288 45

Unlike 13-cis-retinoic acid, the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide] induces apoptosis of neuroblastoma cells by mechanisms involving retinoic acid receptors and oxidative stress. After screening a cDNA array for apoptosis-related genes, the Bcl2-related protein Bak was identified as a fenretinide-inducible gene in SH-SY5Y neuroblastoma cells, and this was confirmed by Western blotting and flow cytometry. Although fenretinide acts synergistically in vitro with chemotherapeutic drugs, these drugs did not induce Bak expression. Retinoic acid receptor antagonists did not block the induction of Bak by fenretinide. Conversely, Bak induction was blocked by the antioxidant vitamin C. Overexpression of Bak increased apoptosis in both the presence and absence of fenretinide, whereas expression of antisense Bak inhibited fenretinide-induced apoptosis. Bak expression was also induced in cells overexpressing the stress-induced transcription factor GADD153, but Bak expression was inhibited in cells expressing an antisense GADD153 construct. These results suggest that Bak is a downstream mediator of an oxidative stress pathway leading to apoptosis of SH-SY5Y neuroblastoma cells in response to fenretinide.
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PMID:Bak: a downstream mediator of fenretinide-induced apoptosis of SH-SY5Y neuroblastoma cells. 1461 28

Fenretinide induces apoptosis of neuroblastoma cells in vitro and interacts synergistically with the chemotherapeutic drugs cisplatin and etoposide. The stress-inducible transcription factor known as growth and DNA damage (GADD)-inducible transcription factor 153 is induced in response to fenretinide and in other cell types modulates apoptosis via pro- and antiapoptotic members of the BCL2 family. Because BCL2-family proteins are important in apoptosis induced by chemotherapeutic drugs, GADD153 may be a key mediator of synergy between fenretinide and chemotherapeutic drugs. To investigate this, GADD153 cDNA in sense and antisense orientations was stably transfected into SH-SY5Y neuroblastoma cells using a tetracycline-inducible vector. Increased expression of GADD153 raised the background level of apoptosis and increased apoptosis induced by fenretinide or the chemotherapeutic drugs cisplatin and etoposide. However, there was no increase in synergy between fenretinide and chemotherapeutic drugs. Conversely, expression of antisense-GADD153 virtually abolished the induction of apoptosis in response to fenretinide but overall had no significant effect on apoptosis induced by chemotherapeutic drugs. The effect of antisense-GADD153 on synergy between chemotherapeutic drugs and fenretinide varied with the drug used: there was no effect on synergy between fenretinide and cisplatin, but the combination of fenretinide with etoposide became antagonistic. These results suggest that mechanisms mediating synergy between fenretinide and chemotherapeutic drugs lie upstream of GADD153.
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PMID:Growth and DNA damage-inducible transcription factor 153 mediates apoptosis in response to fenretinide but not synergy between fenretinide and chemotherapeutic drugs in neuroblastoma. 1464 67

A simple and accurate high-performance liquid chromatography (HPLC) method was developed to measure levels of N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) and its main metabolite N-(4-methoxyphenyl)retinamide (4-MPR) in tissue. Following ultrasonic extraction of fresh tissue in acetonitrile (ACN), 4-HPR and 4-MPR were measured by HPLC with UV absorbance detection at 340 nm, using isocratic elution with ACN, H(2)O, and acetic acid. N-(4-ethoxyphenyl)retinamide (4-EPR) was employed as an internal standard. The 4-HPR and 4-MPR recovery in bovine liver or bovine brain tissue samples spiked with known amounts of 4-HPR and 4-MPR ranged from 93 to 110%. The detection limit of the method was 50 ng/ml. The method was tested on actual samples from an athymic (nu/nu) mouse carrying a subcutaneous tumor xenograft originating from SMS-KCNR neuroblastoma cells. The tissues were harvested and analyzed following a 3 day long treatment with intraperitoneal injections of 4-HPR/Diluent-12. 4-HPR and the metabolite 4-MPR were detected and quantitated in the tested tissues including tumor, liver, and brain. This method can be used to quantify 4-HPR and 4-MPR in different tissues to determine the bioavailability of 4-HPR.
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PMID:Liquid chromatography method for quantifying N-(4-hydroxyphenyl)retinamide and N-(4-methoxyphenyl)retinamide in tissues. 1526 5

Fenretinide, which mediates apoptosis in neuroblastoma cells, is being considered as a novel therapeutic for neuroblastoma. The cytotoxic mechanisms of fenretinide, however, have not been fully elucidated. Sustained-activation of JNK and p38 MAPK signaling has been shown recently to have a pivotal role in stress-induced apoptosis. Whether fenretinide activates the signaling in neuroblastoma cells is not known. In the present study, fenretinide induced sustained-activation of both JNK and p38 MAPK in neuroblastoma cells. Pretreatment with the antioxidant L-ascorbic acid almost completely inhibited the accumulation of fenretinide-induced intracellular reactive oxygen species (ROS), activation of JNK and p38 MAPK and apoptosis. Intracellular ROS production and activation of stress signaling was not altered by fenretinide in resistant neuroblastoma cells. Our study demonstrates that in neuroblastoma cells, fenretinide induces sustained-activation of JNK and p38 MAPK in an ROS-dependent manner and indicates that JNK and p38 MAPK signaling might mediate fenretinide-induced apoptosis. Our results also indicate that suppression of the fenretinide-induced ROS productive system and the downstream JNK and p38 MAPK signaling pathways causes neuroblastoma cells to become resistant to fenretinide.
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PMID:Fenretinide induces sustained-activation of JNK/p38 MAPK and apoptosis in a reactive oxygen species-dependent manner in neuroblastoma cells. 1535 33

Synthetic retinoids such as fenretinide [N-(4-hydroxyphenyl)retinamide] induce apoptosis of neuroblastoma cells, act synergistically with chemotherapeutic drugs, and may provide opportunities for novel approaches to neuroblastoma therapy. Fenretinide-induced cell death of neuroblastoma cells is caspase dependent and results in the release of cytochrome c from mitochondria independently of changes in permeability transition. This is mediated by a signaling pathway characterized by the generation of reactive oxygen species (ROS) via 12-lipoxygenase (12-LOX), and an oxidative-stress-dependent induction of the transcription factor, GADD153 and the BCL2-related protein BAK. Upstream events of fenretinide-induced signaling involve increased levels of ceramide as a result of increased sphingomyelinase activity, and the subsequent metabolism of ceramide to gangliosides via glucosylceramide synthase and GD3 synthase. These gangliosides may be involved in the regulation of 12-LOX leading to oxidative stress and apoptosis via the induction of GADD153 and BAK. The targeting of sphingomyelinases or downstream effectors such as 12-LOX or GADD153 may present novel approaches for the development of more effective and selective drugs for neuroblastoma therapy.
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PMID:Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells. 1565 Feb 34

Fenretinide is thought to induce apoptosis via increases in ceramide levels but the mechanisms of ceramide generation and the link between ceramide and subsequent apoptosis in neuroblastoma cells is unclear. In SH-SY5Y neuroblastoma cells, evidence suggests that acid sphingomyelinase activity is essential for the induction of ceramide and apoptosis in response to fenretinide. Downstream of ceramide, apoptosis in response to fenretinide is mediated by increased glucosylceramide synthase activity resulting in increased levels of gangliosides GD3 and GD2 via GD3 synthase. GD3 is a key signalling intermediate leading to apoptosis via the activation of 12-Lipoxygenase, and the parallel induction of GD2 suggests that fenretinide might enhance the response of neuroblastoma to therapy with anti-GD2 antibodies.
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PMID:The role of gangliosides in fenretinide-induced apoptosis of neuroblastoma. 1590 65

Fenretinide induces apoptosis in SH-SY5Y neuroblastoma cells via a signaling pathway involving the production of reactive oxygen species (ROS), 12-lipoxygenase activity and the induction of the GADD153 transcription factor. NF-kappa B is a key element of many cell signaling pathways and adopts a pro- or anti-apoptotic role in different cell types. Studies have suggested that NF-kappa B may play a pro-apoptotic role in SH-SY5Y cells, and in other cell types NF-kappa B activation may be linked to lipoxygenase activity. The aim of this study was to test the hypothesis that NF-kappa B activity mediates fenretinide-induced apoptosis in SH-SY5Y neuroblastoma cells. Using a dominant-negative construct for Ikappa Balpha stably transfected into SH-SY5Y cells, we show that apoptosis, but not the induction of ROS, in response to fenretinide was blocked by abrogation of NF-kappa B activity. In parental SH-SY5Y cells, fenretinide induced NF-kappa B activity and Ikappa Balpha phosphorylation. These results suggest that NF-kappa B activity links fenretinide-induced ROS to the induction of apoptosis in SH-SH5Y cells, and may be a target for the future development of drugs for neuroblastoma therapy.
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PMID:The NF-kappaB pathway mediates fenretinide-induced apoptosis in SH-SY5Y neuroblastoma cells. 1590 11

Fenretinide (4-HPR) is a synthetic retinoid whose apoptosis-inducing effects have been demonstrated in many tumor types. The precise mechanism of its apoptotic action is not fully understood. To further study the mechanism by which 4-HPR exerts its biological effects in neuroblastoma (NB) and to identify the genes that contribute to the induction of apoptosis, we determined the sensitivity of eight NB cell lines to 4-HPR. Additionally, cDNA microarray analysis was performed on a 4-HPR-sensitive cell line to investigate the temporal changes in gene expression, primarily focusing on the induction of proapoptotic genes. BBC3, a transcriptionally regulated proapoptotic member of the BCL2 family, was the most highly induced proapoptotic gene. Western analysis confirmed the induction of BBC3 protein by 4-HPR. Furthermore, the induction of BBC3 was associated with the sensitivity to this agent in the cell lines tested. Finally we demonstrated that BBC3 alone is sufficient to induce cell death in the 4-HPR-sensitive and resistant NB cell lines, and that siRNA against BBC3 significantly decreases apoptosis induced by 4-HPR. Our results indicate that BBC3 mediates cell death in NB cells in response to 4-HPR.
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PMID:BBC3 mediates fenretinide-induced cell death in neuroblastoma. 1609 45


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