Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells

Holman, David H.; Turner, Lorianne S.; El-Zawahry, Ahmed; Elojeimy, Saeed; Liu, Xiang; Bielawski, Jacek; Szulc, Zdzislaw M.; Norris, Kristi L.; Zeidan, Youssef H.; Hannun, Yusuf A.; Bielawska, Alicja; Norris, James S.

doi:10.1007/s00280-007-0465-0

Cited by 76 publications

(76 citation statements)

References 40 publications

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“…Prominent examples are daunorubicin, etoposide and tamoxifen, which appear, at least in part, to act via ceramide-induced apoptosis [65,181,[202][203][204][205][206]. Further promising agents to treat cancer are inhibitors for enzymes that metabolize ceramide, such as ceramidase or glucosyl-transferase ( Figure 2) [207][208][209][210][211]. Ceramide itself is rather difficult to use as a drug because of its poor water solubility and rapid physiological degradation.…”

Section: Sphingolipid Biosynthesis In the Endoplasmic Reticulum: Enzymentioning

confidence: 99%

Ceramide signaling in cancer and stem cells

Bieberich

2008

Future Lipidology

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Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/ sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells. Keywordsapoptosis; cancer; cell polarity; ceramide; ES cells; lipid rafts; sphingomyelin; sphingosine-1-phosphate Ceramide & its derivatives: from metabolism to cell signalingThe structural core of ceramide is the sphingoid base sphingosine (Figure 1), a lipid that is synthesized from the amino acid serine and the activated fatty acid palmitoyl-CoA (Figure 2). Sphingosine (or sphingenine) was first isolated and characterized by the German pathologist and 'father of neurochemistry ' Johann Ludwig Wilhelm Thudichum (1829-1901 [1,2]. He coined the term sphingolipids, which is derived from 'sphingos', the genitive of Sphinx. In Greek, 'sphingo' means 'to strangle'. According to the legend, a fate of death was meant for everyone who could not solve the riddles posed by the Sphinx. Quite ironically, this is how many sphingolipid researchers may feel when faced with analyzing the function of ceramide. The riddle of ceramide, its function and how it acts as signaling lipid, is far from being solved. To ease our fears when confronted with the Sphinx in sphingolipid biochemistry, a related Greek word, 'sphingein', meaning 'to bind tight', alludes to the possibility of solving the enigma of ceramide by identifying its binding proteins.In addition to ceramide, more than a hundred different sphingolipids are known. The most comprehensive collection of sphingolipids, with respect to their characteristics and structures, can be found at [401], a Webpage supported by the National Institutes of General Medical Sciences [3,4]. Sphingolipids are essential components of cellular membranes and have been (Figure 3) . Among these, their roles as pro-or anti-apoptotic and pro-or anti-proliferative signaling lipids are the most important. Most recently, our group has found that establishment of cell polarity during embryonic development is another biological process regulated by sphingolipids [28]. To define a profile of functions for individual sphingolipids is difficult because of their rapid metabolic interconversion. To add to this predicament, several derivatives of ceramide have functions similar to ceramide itself. Hence, novel techniques are need...

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Section: Sphingolipid Biosynthesis In the Endoplasmic Reticulum: Enzymentioning

confidence: 99%

Ceramide signaling in cancer and stem cells

Bieberich

2008

Future Lipidology

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“…We demonstrate here, using live-cell studies, that a cationic fluorescently labeled calixarene (NBDCalAm) acts as a lysosomotropic compound without any induction of cell death, unlike other previously described lysosomotropic compounds (21,22). Thus this NBDCalAm provides us with a novel, remarkable easy to use, exciting tool to investigate lysosomal function and kinetics in living cells over longer periods of time.…”

mentioning

confidence: 99%

Stable and sensitive probes for lysosomes: Cell‐penetrating fluorescent calix[4]arenes accumulate in acidic vesicles

et al. 2010

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The uptake of a fluorescently labeled cationic calix [4] (NBDCalAm) in live, nonfixed cells has been investigated. The compound is taken into the cells rapidly and shows distinct endosomal distribution after 2 hours. This distribution pattern shows colocalization with lysosomal staining. The uptake is not altered by inhibition of clathrin or caveolae dependent pathways nor by depletion of the cellular ATP-pool. Immediately after uptake the probe is localized in the Golgi and brefeldin A treatment prevents transport to lysosomes. Pulse chase experiments with bafilomycin A1, monensin, and sodium azide showed that accumulation and retention of the probe in lysosomes is primarily driven by the activity of vacuolar ATPases. The NBD labeled calix[4]arene provides a very stable and sensitive marker for lysosomes, and has a considerable advantage over some commercially available lysosomal markers in so far that the fluorescent signal is stable even when the cells are incubated in dye-free medium after staining. ' 2010 International Society for Advancement of Cytometry Key termslysosome; calixarene; cell-penetration; immunofluorescence CALIXARENES (1) are a family of readily synthesized and functionalized macrocycles which have found applications in a number of research areas. In particular the ability of derivatives to complex anions (2,3) and cations (4,5) has been exploited for the development of sensors. Recently, interest has focused on the use of calixarene derivatives in biological systems be it as drugs, drug delivery systems, or imaging agents. In the design of drug molecules, particular attention has been paid to calixarenes as antimicrobials (6-8), as vaccines (9) and as anticancer agents (10). In the field of drug delivery, agents for nucleic acids based on single calixarenes (11-13) have shown promise and we have recently shown that larger arrays of cationic calix[4]arene, so-called multicalixarenes, are able to transfect DNA effectively (14). In addition a number of studies have combined the ability of calixarene derivatives to complex cations with their low toxicity in the development of noncovalently labeled protein MRI imaging agents (15,16).While the nontoxic (17) and non-immunogenicity (18,19) status of calixarenes has been established, less information is available on how calixarenes are processed within cells and their cellular fate, both of which are important features which must be characterized before such derivatives are taken further for clinical development. We recently demonstrated that fluorescently labeled calix [4]arene have the potential to track progress of the macrocycle in cells, as an NBD labeled cationic derivative was readily and speedily taken up into cells and provided a very stable, nontoxic read-out system to investigate cellular localization (20). The absorbance and emission spectra for the NBDCalAm showed that it can easily be visualized using a GFP filter (20).

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“…Kanserli prostat hücrelerinde radyasyon terapisi sırasında seramidaz enzim düzeyinin arttığı ve bu artışın ilaç-la tedaviye ve radyasyon terapisine karşı direnç oluşturduğu tespit edilmiştir (12,18). Seramidaz enziminin baskılanmasının kanserli prostat hücrelerinde apoptozu uyardığı ve kanser büyümesini engellediği gösterilmiştir (19,20). Kanserli karaciğer hücrelerinde de benzer şekil-de seramidaz enzim aktivitesinin baskılanması-nın kanser ilaçlarına olan direnci azalttığı tespit edilmiştir (21).…”

Section: şEki̇lunclassified

Hepatosellüler Karsi̇nom Hücreleri̇nde Karmofurun Si̇totoksi̇k Ve Apoptoti̇k Etki̇leri̇

Kuş¹

2017

Kocatepe Tıp Dergisi

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Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells

Abstract: These results provide evidence that treatment with molecules such as LCL204, which restore ceramide levels in PCa cells may serve as a new viable treatment option for PCa.

Cited by 76 publications

References 40 publications

Ceramide signaling in cancer and stem cells

Ceramide signaling in cancer and stem cells

Stable and sensitive probes for lysosomes: Cell‐penetrating fluorescent calix[4]arenes accumulate in acidic vesicles

Hepatosellüler Karsi̇nom Hücreleri̇nde Karmofurun Si̇totoksi̇k Ve Apoptoti̇k Etki̇leri̇

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