Increase of Ceramide and Induction of Mixed Apoptosis/Necrosis by N-(4-Hydroxyphenyl)- retinamide in Neuroblastoma Cell Lines

Bj, Maurer; Ls, Metelitsa; Rc, Seeger; Mc, Cabot; Reynolds, C. Patrick

doi:10.1093/jnci/91.13.1138

Cited by 263 publications

(230 citation statements)

References 58 publications

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“…Previously, Radin has reported that the inhibition of GCS with PDMP, a glucosylceramide analog, results in an increase in the levels of ceramide and sphingosine and also a decrease in protein kinase C levels in mouse Ehrlich ascites carcinoma cells and in rat glioma cells, that is, GCS inhibition enhances the anti-proliferative effects of chemotherapeutics on cancer cells [71,72]. Maurer et al [73] have also reported that GCS inhibition increases the intracellular ceramide levels and enhances the cytotoxic effects of 4-HPR and safingol in tumor cells. Not only in vitro but also in vivo studies have shown that progression of melanoma cells decreases in response to GCS suppression, and thus P-gp inhibition [74,75].…”

Section: Glucosylceramide Synthase In Cancer Therapymentioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

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Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDPglucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

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Section: Glucosylceramide Synthase In Cancer Therapymentioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

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“…Accordingly, while apoptosis by HPR appears receptor-independent (Delia et al, 1993;Kitareewan et al, 1999), and actually correlates with the ability of HPR to elicit intracellular free radicals and acidi®cation (Delia et al, 1997a;Angoli et al, 1996;Maurer et al, 1999;Suzuki et al, 1999), transcriptional regulation of target genes (e.g. AP1) is retinoid-receptor dependent, according to data showing that HPR selectively activates the transcription by RAR-g, to a less extent by RAR-b, but not by RAR-a (Fanjul et al, 1996;Kazmi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

et al. 2000

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The cancer chemopreventive synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the growth and induce apoptosis of tumor cells. In this study we analysed the growth suppressive e ect of HPR on human breast cancer cell lines in vitro and the role of the retinoblastoma protein (pRb) in this response. Treatment of MCF7, T47D and SKBR3 for 24 ± 48 h with 3 mM HPR, a concentration attainable in vivo, resulted in growth inhibition and marked dephosphorylation of pRb involving Ser 612 , Thr 821 , Ser 795 and Ser 780 , target residues for cyclin-dependent kinase 2 (Cdk2) the former two, and Cdk4 the latter two. Interestingly, this dephosphorylation of pRb occurred in S-G2-M phase cells, as revealed by experiments on cells fractionated by FACS according to the cell cycle phase, hence suggesting that the retinoid interferes with the regulation of pRb phosphorylation. The in vitro phosphorylation of a GST-pRb recombinant substrate by Cdk2 immunocomplexes from MCF7, T47D and SKBR3 was markedly suppressed after HPR treatment, whereas that by Cdk4 complexes was suppressed in T47D and SKBR3 but not in MCF7. The steady-state levels of Cdk2, Cdk4 and Cyclin A proteins were una ected by HPR, while those of Cyclin D1 were signi®cantly reduced in all three cell lines. Interestingly, Cyclin D1 downregulation by HPR correlated with transcriptional repression, but not with enhanced proteolysis of Cyclin D1 typically elicited by other retinoids. Collectively, our data suggest that the antiproliferative activity of HPR arises from its capacity to maintain pRb in a de-phosphorylated growthsuppressive status in S-G2/M, possibly through Cyclin D1 downregulation and inhibition of pRb-targeting Cdks.

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“…Evidence supporting a role for ceramide during 4HPR action on HL-60 leukaemia cells and neuroblastoma cells is based on studies demonstrating an elevation of cellular ceramide levels in response to 4HPR and the ability of the ceramide synthase inhibitor fumonisin B 1 (FB 1 ) to block this ceramide response and prevent 4HPR-induced apoptosis (DiPietrantonio et al, 1998;Maurer et al, 1999). However, in other instances where induction of apoptosis is accompanied by an elevation of ceramide, FB 1 failed to prevent the apoptotic response while blocking ceramide production (Nagy et al, 2000;Miguet et al, 2001).…”

mentioning

confidence: 99%

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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Increase of Ceramide and Induction of Mixed Apoptosis/Necrosis by N-(4-Hydroxyphenyl)- retinamide in Neuroblastoma Cell Lines

Abstract: 4-HPR may form the basis for a novel, p53-independent chemotherapy that operates through increased intracellular levels of ceramide and that retains cytotoxicity under reduced oxygen conditions.

Cited by 263 publications

References 58 publications

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

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

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