Sphingolipid targets in cancer therapy

Modrak, David E.; Gold, David V.; Goldenberg, David M.

doi:10.1158/1535-7163.mct-05-0420

Cited by 122 publications

(97 citation statements)

References 67 publications

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“…This proapoptotic SL is produced by cancer cells in response to exposure to ionizing radiation and most chemotherapeutic agents, however, some chemo-and radioresistant tumor cells exhibit defects in ceramide generation supporting the emerging role of ceramide as a tumor suppressor lipid [3,4]. Strategies that target the enzymes of ceramide clearance (SMS, GCS or ceramidases), resulting in enhanced ceramide levels in cancer cells, have been developed as novel approaches for anticancer chemotherapy.…”

Section: Page 17 Of 43mentioning

confidence: 99%

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The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Salma

Lafont

Therville

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 AbstractMarine environment has frequently afforded a variety of biologically active compounds with strong anticancer and cytotoxic properties. In the present study, the mechanism of action of Jaspine B, an anhydrophytosphingosine derivative isolated from the marine sponge Jaspis sp., was investigated. Jaspine B was able to doseand time-dependently decrease the viability of murine B16 and human SK-Mel28 melanoma cells. On these cells, Jaspine B treatment triggered cell death by typical apoptosis as illustrated by phosphatidylserine externalization, the release of cytochrome c and caspase processing. These effects were associated with increased intracellular ceramide levels owing to perturbed ceramide metabolism. Indeed, Jaspine B exposure strongly inhibited the activity of sphingomyelin synthase (SMS), an enzyme that converts de novo ceramide into the membrane lipid sphingomyelin.Moreover, whereas Jaspine B-induced cell death was enhanced in SMS1-depleted cells, it was strongly inhibited in cells that stably overexpress human SMS1. Finally, the cytotoxic effects of Jaspine B truncated analogs were also shown to be dependent on SMS activity.Altogether, Jaspine B is able to kill melanoma cells by acting on SMS activity and consequently on ceramide formation, and may represent a new class of cytotoxic compounds with potential applications in anticancer melanoma therapy.

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Section: Page 17 Of 43mentioning

confidence: 99%

“…Manipulation of cellular sphingolipid (SL) metabolism has been proposed as a means to amplify or restore apoptosis [3]. Indeed, numerous studies have shown that increased intracellular levels of the SL metabolite ceramide inhibit cell proliferation and promote apoptosis of tumor cells (reviewed in [4]).…”

Section: Introductionmentioning

confidence: 99%

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Salma

Lafont

Therville

et al. 2009

Biochemical Pharmacology

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“…Ceramide mediates a wide array of stress signals such as anticancer treatments leading to apoptosis, whereas S1P exerts prosurvival capabilities by antagonizing ceramide effects (Modrak et al, 2006). So a ceramide/S1P rheostat has been hypothesized to determine the fate of cell, such that the relative cellular concentrations of ceramide and S1P determine whether a cell proliferates or undergoes apoptosis (Andrieu-Abadie and Levade, 2002;Reynolds et al, 2004;Bieberich et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Reversion of Multidrug Resistance by SKI-II in SGC7901/DDP Cells and Exploration of Underlying Mechanisms

Zhu¹,

Zhu²,

Cai³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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In order to investigate whether SKI-II could reverse drug resistance and its possible mechanisms, we treated SGC7901/DDP cells with SKI-II or SKI-II in combination with DDP. Then cell growth, apoptosis, micromorphological changes, and expression of SphK1, P-gp, NF-κB, Bcl-2 and Bax were assessed by MTT assay, flow cytometry, electron microscopy, immunocytochemistry and Western blot assay respectively. SGC7901/DDP cells were insensitive to cisplatin 2.5mg/L, but when pretreated with SKI-II, their proliferation was inhibited by cisplatin 2.5mg/L significantly, the inhibition rate increasing with time and dose. The apoptosis rate was also significantly elevated. Expression of SphK1 and P-gp was decreased significantly, Pearson correlation analysis showing significant correlation between the two (r=0.595, P<0.01). Expression of NF-κB and Bcl-2 was decreased significantly,while that of Bax was increased, compared to the control group. There were significant correlations between SphK1 and NF-κB(r=0.723, P<0.01), NF-κB and Bcl-2(r=0.768, P<0.01). All these data indicated that SKI-II could reverse drug resistance of SGC7901/DDP to cisplatin by down-regulating expression of P-gp and up-regulating apoptosis through down-regulation of SphK1. The increased apoptotic sensitivity of SGC7901/ DDP to cisplatin was due to the decreasing proportion of Bcl-2/Bax via down-regulating NF-κB.

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“…GCS catalyzes the first step in the biosynthesis of glycosphingolipids, and its cellular activity modulates the levels of the other lipids as well as ceramide (7)(8)(9). Early studies demonstrated that increasing the capacity for ceramide glycosylation in GCS-transfected human breast cancer MCF-7 cells conferred greater resistance to doxorubicin and to TNF-· (10,11).…”

Section: Introductionmentioning

confidence: 99%

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Madden¹

2011

Int J Oncol

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Abstract. Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at nontoxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug reisistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.

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Sphingolipid targets in cancer therapy

Cited by 122 publications

References 67 publications

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Reversion of Multidrug Resistance by SKI-II in SGC7901/DDP Cells and Exploration of Underlying Mechanisms

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

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