Novel analogs of d-e-MAPP and B13. Part 2: Signature effects on bioactive sphingolipids

Bielawska, Alicja; Bielawski, Jacek; Szulc, Zdzisław M.; Mayroo, Nalini; Liu, Xiang; Bai, Aiping; Elojeimy, Saeed; Rembiesa, Barbara; Pierce, Jason S.; Norris, James S.; Hannun, Yusuf A.

doi:10.1016/j.bmc.2007.08.032

Cited by 66 publications

(69 citation statements)

References 65 publications

(47 reference statements)

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“…The latter results, although unexpected for AC inhibitors, are not unprecedented. Bielawska et al ( 55 ) reported that the sphingolipid profi les of MCF-7 cells treated with different ceramidase inhibitors derived from B13 and D-e-MAPP followed different patterns depending on the chemical function substituted for the original amide. In the case of an N -alkyl analog of D-e-MAPP, namely, compound LCL284, ceramides accumulated, but long chain bases did not change signifi cantly.…”

Section: Discussionmentioning

confidence: 99%

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Camacho

Meca-Cortés

Abad

et al. 2013

Journal of Lipid Research

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Supplementary key words ceramide • metastasis • inhibitorsCancer cells develop a lipogenic phenotype that supports the energy and membrane synthesis requirements associated with the enhanced proliferation and survival under stress inherent to malignant progression ( 1, 2 ). The recognition of the importance of this phenotype in cancer has led to the use of enzymes of lipid metabolism as markers to monitor neoplastic progression and response to therapy, as well as to the development of drugs targeted at key lipogenic enzymes, such as fatty acid synthase (FASN) ( 2, 3 ). The excess fatty acid synthesis that results from the coordinated activation of lipogenic enzymes in many types of cancer leads to the accumulation of palmitate, which needs to be further processed by the cells due to the toxic effects of its accumulation. One pathway that Abstract Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confi rm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specifi c AC inhibitors could act by counteracting critical growth properties of SAF2008-00706 and SAF2011-22444 (to G.F.) Press, February 18, 2013 DOI 10.1194 Acid ceramidase as a therapeutic target in metastatic prostate cancer Abbreviations: AC, acid ceramidase; CMH, ceramide monohexoside; MDR1, multidrug resistant protein 1; NC, neutral ceramidase; PC, prostate cancer; PIN, prostate intraepithelial neoplasia; S1P, sphingosine-1-phosphate. This work was supported by Ministry of Science and Innovation Grants ; Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1072 (to G.F.); Ministry of Science and Innovation Grants SAF2008-04136-C02-01 and SAF2011-24686 (to T.M.T.); Ministry of Economy and Competitivity Grant SAF2012-40017-C02-01 (to T.M.T.); Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1482 (to T.M.T.); Xarxa de Bancs de Tumours de Catalunya-Pla Director d'Oncologia and Fondo Europeo de Desarrollo...

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Section: Discussionmentioning

confidence: 99%

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Camacho

Meca-Cortés

Abad

et al. 2013

Journal of Lipid Research

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“…P-gp is an anti-apoptotic membrane glycoprotein encoded by the MDR-1 gene, which could reduce the accumulation of chemotherapeutic drug in cells. P-gp could transport lots of hydrophobic lipophilic drugs such as colchicine, doxorubicin, vincristine out of cells using the energy released by ATP hydrolysis actively, decreased the intracellular drug concentration, redistributed the drugs, this all could lead to drug resistance (Veldman, 2004;Szulc, 2006;Bielawska, 2008). In a recent study, overexpression of SphK1 in RBE-4 cerebral endothelial cells was shown to enhance the expression of P-gp at the mRNA and protein levels.…”

Section: Discussionmentioning

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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“…It was shown that application of ceramide analogs or their mimetics induces apoptosis and/or growth arrest in various types of cancer cells (Bielawska et al 2008;Szulc et al 2006). It was clearly shown that there was significant inhibition of tumor growth and progression in response to ceramidoids, a recently synthesized ceramides, in head and neck squamous cancer cells and some other cancer models, in vivo (Bielawska et al 2008;Senkal et al 2006). Different structural analogs of ceramides have also been shown to induce apoptosis in breast cancer cells (Struckhoff et al 2004) and drug-resistant MCF-7/Adr cells (Crawford et al 2003).…”

Section: Discussionmentioning

confidence: 99%

The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60 acute myeloid leukemia cells

Çakır

Saydam

Şahin

et al. 2010

J Cancer Res Clin Oncol

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Purpose Acute promyelocytic leukemia results from a translocation between 15 and 17 chromosomes that produce PML/RARa fusion protein. PML/RARa inhibits differentiation of myeloid precursor cells at stem cell level. Resveratrol is a phytoalexin that exerts cytotoxic effects on cancer cells. Ceramides have crucial roles in cell growth, proliferation, differentiation, drug resistance, and apoptosis. In this study, we examined the possible cytotoxic effects of resveratrol on acute myeloid leukemia cells and determined the roles of ceramide-metabolizing genes in resveratrol-induced apoptosis, in addition to investigating the possibility of increasing the sensitivity of HL60 cells to resveratrol by manipulating sphingolipids. Methods Cytotoxic effects of resveratrol, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by RT-PCR. Results The results revealed that manipulations of ceramide metabolism toward generation or accumulation of apoptotic ceramides increased apoptotic effects of resveratrol in HL60 cells, synergistically. More importantly, gene expression analyses revealed that resveratrol-induced apoptosis via increasing expression levels of ceramidegenerating genes and decreasing expression levels of antiapoptotic sphingosine kinase-1 and glucosylceramide synthase genes. Conclusion These results showed for the first time that increasing intracellular levels of ceramides by biochemical approaches has also increased sensitivity of HL60 cells to resveratrol. We also showed that resveratrol induces apoptosis through manipulating ceramide-metabolizing genes that resulted in the accumulation of ceramides in HL60 cells.

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Novel analogs of d-e-MAPP and B13. Part 2: Signature effects on bioactive sphingolipids

Cited by 66 publications

References 65 publications

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Acid ceramidase as a therapeutic target in metastatic prostate cancer

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

The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60 acute myeloid leukemia cells

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