Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report

Norris, James S.; Bielawska, Alicja; Day, Terry A.; El-Zawahri, A; Elojeimy, Saeed; Hannun, Yusuf A.; Holman, David H.; Hyer, Marc L.; Landon, Chelsea D.; Lowe, S; Dong, John Y.; McKillop, John; Norris, Kristi L.; Obeid, Lina M.; Rubinchik, Semyon; Tavassoli, Mahvash; Tomlinson, Stephen; Voelkel‐Johnson, Christina; Liu, X

doi:10.1038/sj.cgt.7700965

Cited by 55 publications

(46 citation statements)

References 38 publications

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“…(C) Effect of the protease inhibitors leupeptin, CA074, and pepstatin A on acid ceramidase protein levels following a 6 h treatment with 10 lM desipramine. since acid ceramidase has been shown to be over-expressed in cancer and to play an important role in mediating resistance to chemotherapeutics [18,19,22].…”

Section: Discussionmentioning

confidence: 99%

New insights on the use of desipramine as an inhibitor for acid ceramidase

et al. 2006

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Treatment of different cancer cell lines with desipramine induced a time-and dose-dependent downregulation of acid ceramidase. Desipramine's effect on acid ceramidase appeared specific for amphiphilic agents (desipramine, chlorpromazine, and chloroquine) but not other lysomotropic agents such as ammonium chloride and bafilomycin A1, and was not transcriptionally regulated. The cathepsin B/L inhibitor, CA074ME, but not the cathepsin D inhibitor, pepstatin A, blocked desipramine's effect on acid ceramidase. Desipramine led to a more pronounced downregulation of sphingosine compared to ceramide suggesting acid ceramidase inhibition is important to desipramine's mechanism of action. This study reveals a new mechanism of action for desipramine.

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Section: Discussionmentioning

confidence: 99%

New insights on the use of desipramine as an inhibitor for acid ceramidase

et al. 2006

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“…Specifi cally, the expression levels of AC in prostate cancer have been reported to be elevated relative to normal prostate tissue ( 16,17 ). Prostate cancer (PC) is the most prevalent neoplasia in men in industrialized nations ( 18 ).…”

Section: Papain Activitymentioning

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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“…7,8 These include the application of cell permeable short-chain Cers, 9-11 liposomal formulations, 12, 13 site-specific cationization 14-17 and induction of endogenous Cer by modulation of SPL metabolizing enzymes. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] In the course of our investigation of SPLs chemistry and the search for new molecules that mimic the action of SPLs and/or regulate their metabolism, we have focused on analogs that affect Cer metabolism, especially the Cer-Sph-S1P balance, and display particular desired properties, and we have also attempted to target them to specific sub-cellular compartments. 14-17, 27, 28, 31…”

Section: Introductionmentioning

confidence: 99%

Novel analogs of d-e-MAPP and B13. Part 1: Synthesis and evaluation as potential anticancer agents

Szulc

Mayroo

Bai

et al. 2008

Bioorganic & Medicinal Chemistry

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A series of novel isosteric analogs of the ceramidase inhibitors, (1S, 2R)-N-myristoylaminophenylpropanol-1 (D-e-MAPP) and (1R, 2R)-N-myristoylamino-4′-nitro-phenylpropandiol-1, 3 (B13), with modified targeting and physicochemical properties were designed, synthesized, and evaluated as potential anticancer agents. When MCF7 cells were treated with the analogs, results indicated that the new analogs were of equal or greater potency compared to the parent compounds. Their activity was predominantly defined by the nature of the modification of the N-acyl hydrophobic interfaces: N-acyl analogs (class A), urea analogs (class B), N-alkyl analogs (class C, lysosomotropic agents) and ω-cationic-N-acyl analogs (class D, mitochondriotropic agents). The most potent compounds belonged to either class D, the aromatic ceramidoids, or to class C, the aromatic Nalkylaminoalcohols. Representative analogs selected from this study were also evaluated by the National Cancer Institute in Vitro Anticancer Drug Discovery Screen. Again, results showed a similar class-dependent activity. In general, the active analogs were non-selectively broad spectrum and had promising activity against all cancer cell lines. However, some active analogs of the D-e-MAPP family were selective against different types of cancer. Compounds LCL85, 120, 385, 284, and 204 were identified to be promising lead compounds for therapeutic development.

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Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report

Cited by 55 publications

References 38 publications

New insights on the use of desipramine as an inhibitor for acid ceramidase

New insights on the use of desipramine as an inhibitor for acid ceramidase

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Novel analogs of d-e-MAPP and B13. Part 1: Synthesis and evaluation as potential anticancer agents

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