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ES 285

Spisulosine (ES-285), isolated from the sea mollusc Spisula polynyma, in the prostate tumor PC-3 and LNCaP cell lines. Spisulosine inhibited cell proliferation with an IC50 of 1 microM in both cell lines, although it was more effective in the androgen-independent PC-3 cells. The anti-proliferative effect induced by Spisulosine in prostate cells was independent of peroxisome proliferator activated receptor gamma (PPARgamma) and phosphatidylinositol 3-kinase/(PI3K/Akt), Jun N-terminal kinase (JNK), p38 or classical protein kinase C (PKCs) pathways, as it was inferred from the results obtained with specific inhibitors of these routes. However, Spisulosine treatment of prostate cells induced an increase in the intracellular ceramide levels, that was totally blocked by the ceramide synthase inhibitor Fumonisin B1, indicating that the ceramide accumulation came from the de novo biosynthesis. Spisulosine also induced in both PC-3 and LNCaP cells, an activation of the atypical PKC isoform, PKCzeta, which is one of the target proteins of ceramide. These results indicate that the marine compound Spisulosine inhibits the growth of the prostate PC-3 and LNCaP cells through intracellular ceramide accumulation and PKCzeta activation. see: http://www.ncbi.nlm.nih.gov/pubmed/18343365.

Current developer:    PharmaMar USA, Inc.

 1: Baird RD, Kitzen J, Clarke PA, Planting A, Reade S, Reid A, Welsh L, López Lázaro L, de las Heras B, Judson IR, Kaye SB, Eskens F, Workman P, deBono JS, Verweij J. Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors. Mol Cancer Ther. 2009 Jun;8(6):1430-7. Epub 2009 Jun 9. PubMed PMID: 19509256.

2: Singh R, Sharma M, Joshi P, Rawat DS. Clinical status of anti-cancer agents derived from marine sources. Anticancer Agents Med Chem. 2008 Aug;8(6):603-17. Review. PubMed PMID: 18690825.

3: Sánchez AM, Malagarie-Cazenave S, Olea N, Vara D, Cuevas C, Díaz-Laviada I. Spisulosine (ES-285) induces prostate tumor PC-3 and LNCaP cell death by de novo synthesis of ceramide and PKCzeta activation. Eur J Pharmacol. 2008 Apr 28;584(2-3):237-45. Epub 2008 Feb 14. PubMed PMID: 18343365.

4: Salcedo M, Cuevas C, Alonso JL, Otero G, Faircloth G, Fernandez-Sousa JM, Avila J, Wandosell F. The marine sphingolipid-derived compound ES 285 triggers an atypical cell death pathway. Apoptosis. 2007 Feb;12(2):395-409. PubMed PMID: 17191124.

5: Faircloth G, Cuevas C. Kahalalide F and ES285: potent anticancer agents from marine molluscs. Prog Mol Subcell Biol. 2006;43:363-79. Review. PubMed PMID: 17153351.

6: Den Brok MW, Nuijen B, García JL, Miranda E, Calvo P, Manada C, Beijnen JH. Compatibility and stability of the novel anticancer agent ES-285 x HCl formulated with 2-hydroxypropyl-beta-cyclodextrin in infusion devices. Pharmazie. 2006 Jan;61(1):21-4. PubMed PMID: 16454201.

7: Den Brok MW, Nuijen B, Meijer DM, Millán E, Manada C, Beijnen JH. Pharmaceutical development of a parenteral lyophilised formulation of the investigational anticancer agent ES-285.HCl. PDA J Pharm Sci Technol. 2005 Jul-Aug;59(4):246-57. PubMed PMID: 16218203.

8: Stokvis E, Rosing H, López-Lázaro L, Schellens JH, Beijnen JH. A more sensitive MS detector does not obviously lead to a more sensitive assay: experiences with ES-285. Biomed Chromatogr. 2004 Jul;18(6):403-7. PubMed PMID: 15273982.

9: den Brok MW, Nuijen B, Miranda E, Floriano P, Munt S, Manzanares I, Beijnen JH. Development and validation of a liquid chromatography-ultraviolet absorbance detection assay using derivatisation for the novel marine anticancer agent ES-285 x HCl [(2S,3R)-2-amino-3-octadecanol hydrochloride] and its pharmaceutical dosage form. J Chromatogr A. 2003 Dec 12;1020(2):251-8. Erratum in: J Chromatogr A. 2004 Apr 9;1033(1):191. PubMed PMID: 14661748.

10: Maraschiello C, Miranda E, Millán E, Floriano P, Vilageliu J. Phenylisothiocyanate and dansyl chloride precolumn derivatizations for the high-performance liquid chromatography analysis of the antitumoral agent ES-285 in dog plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Jul 5;791(1-2):1-11. PubMed PMID: 12798159.

11: Taguchi T. [Development of marine-derived anti-cancer compounds]. Gan To Kagaku Ryoho. 2003 May;30(5):579-88. Review. Japanese. PubMed PMID: 12795086.

12: Stokvis E, Nan-Offeringa L, Rosing H, López-Lázaro L, Aceña JL, Miranda E, Lyubimov A, Levine BS, D'Aleo C, Schellens JH, Beijnen JH. Quantitative analysis of ES-285, an investigational marine anticancer drug, in human, mouse, rat, and dog plasma using coupled liquid chromatography and tandem mass spectrometry. J Mass Spectrom. 2003 May;38(5):548-54. PubMed PMID: 12794877.

13: Jimeno JM. A clinical armamentarium of marine-derived anti-cancer compounds. Anticancer Drugs. 2002 May;13 Suppl 1:S15-9. Review. PubMed PMID: 12173490.