(1S,2R)-D-erythro-2-(N-Myristoylamino)-1-phenyl-1-propanol as an Inhibitor of Ceramidase

Bielawska, Alicja; Greenberg, Mathew S.; Perry, David K.; Jayadev, Supriya; Shayman, James A.; McKay, Catriona; Hannun, Yusuf A.

doi:10.1074/jbc.271.21.12646

Cited by 200 publications

(137 citation statements)

References 71 publications

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“…The separate addition of these compounds did not generate ceramide release or apoptotic death in either cellular model, as previously described in lymphoid cell lines . Contrary to our findings, Bielawska et al (1996) reported a threefold elevation in ceramide levels after the addition of 20 mM D-MAPP to HL60 cells. Moreover, Raisova et al (2002) reported a twofold elevation in the death rate after 25 mM D-MAPP treatment of HaCaT keratinocytes.…”

Section: Discussioncontrasting

confidence: 55%

“…We have produced evidence that ceramide can induce cell killing by both mitotic and apoptotic mechanisms. It was previously reported that increasing intracellular ceramide levels, either by the inhibition of alkaline ceramidase or by the addition of exogenous C2-ceramide, can induce growth arrest in HL60 cells (Bielawska et al, 1996) and breast tumour cells (Gewirtz, 2000), respectively. In most cases, this G1 arrest further led to mitotic death (McIlwrath et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

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Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

et al. 2004

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

et al. 2004

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“…Incubation of B-CLL cells with 20 mM sphingosine resulted in the killing of B-CLL cells, although this agent was less e ective than C 2 ceramide (Figure 7). D-erythro-2 (N-myristoylamino)-1-phenyl-1-propanol (MAPP) is a potent inhibitor of alkaline ceramidase with an IC 50 of 1 ± 3 mM (Bielawska et al, 1996). Ten micromolar MAPP failed to reduce cell killing by C 2 ceramide (Figure 7).…”

Section: An Inhibitor Of Ceramidase Does Not Abrogate Killing Of B-clmentioning

confidence: 99%

Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism

et al. 1999

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Synthetic ceramides induce apoptotic death of Jurkat and HL60 leukaemia cell lines. By contrast we show here that ceramide induces non-apoptotic killing of malignant cells from patients with B-chronic lymphocytic leukaemia (B-CLL) and of normal B lymphocytes. The protein phosphatase inhibitor okadaic acid readily induces apoptosis of B-CLL cells, indicating that this death pathway is fully functional in these cells. The ability of ceramide to activate the apoptotic protease caspase 3 in HL60 cells but not in B-CLL cells, as well as the lack of correlation of ceramidemediated killing of di erent B-CLL isolates with expression of the apoptosis-regulating proteins bcl-2 and bax reinforce the conclusion that ceramide killing of B-CLL cells is by a non-apoptotic mechanism. Fludarabine treatment or g-irradiation of B-CLL cells resulted in ceramide elevation and in killing by both apoptotic and non-apoptotic mechanisms, suggesting that a ceramide-triggered non-apoptotic mechanism may play a role in the killing of these cells. Therefore, the results here show that ceramide can induce either apoptotic or non-apoptotic death, depending on the cellular context. The inability of synthetic dihydroceramide to kill B-CLL cells or normal B lymphocytes suggests that non-apoptotic killing by ceramide is via interaction with a speci®c, but unidenti®ed, cellular target.

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“…Recently, evidence has emerged to suggest that neutral/ alkaline CDases are involved in the regulation of cell proliferation by production of Sph or decrease of Cer (19,20,34). Coroneos et al (19) revealed that the membrane-associated neutral/alkaline CDase could be activated by several growth factors including platelet-derived growth factor but not cytokines, resulting in an increase of Sph with a consequent stimulation of cell proliferation.…”

Section: Homology Of the Deduced Amino Acid Sequence Of Mouse Neutralmentioning

confidence: 99%

Molecular Cloning of the Full-length cDNA Encoding Mouse Neutral Ceramidase

Tani

Okino

Mori

et al. 2000

Journal of Biological Chemistry

105

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We report here the molecular cloning, sequencing, and expression of the gene encoding the mouse neutral ceramidase, which has been proposed to function in sphingolipid signaling. A full-length cDNA encoding the neutral ceramidase was cloned from a cDNA library of mouse liver using the partial amino acid sequences of the purified mouse liver ceramidase. The open reading frame of 2,268 nucleotides encoded a polypeptide of 756 amino acids having nine putative N-glycosylation sites. Northern blot analysis revealed that the mRNA of the ceramidase was expressed widely in mouse tissues, with especially strong signals found in the liver and kidney. The ceramidase activity of lysates of CHOP cells increased more than 900-fold when the cells were transformed with a plasmid containing the cDNA encoding ceramidase. We also cloned the ceramidase homologue from the cDNA library of mouse brain and found that the sequence of the open reading frame, but not the 5-noncoding region, was identical to that of the liver.

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(1S,2R)-D-erythro-2-(N-Myristoylamino)-1-phenyl-1-propanol as an Inhibitor of Ceramidase

Cited by 200 publications

References 71 publications

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism

Molecular Cloning of the Full-length cDNA Encoding Mouse Neutral Ceramidase

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