title: Enigmol: a novel sphingolipid analogue with anticancer activity against cancer cell lines and in vivo models for intestinal and prostate cancer.
abstract: Sphingoid bases are cytotoxic for many cancer cell lines and are thought to contribute to suppression of intestinal tumorigenesis in vivo by ingested sphingolipids. This study explored the behavior of a sphingoid base analogue, (2S,3S,5S)-2-amino-3,5-dihydroxyoctadecane (Enigmol), that cannot be phosphorylated by sphingosine kinases and is slowly N-acylated and therefore is more persistent than natural sphingoid bases. Enigmol had potential anticancer activity in a National Cancer Institute (NCI-60) cell line screen and was confirmed to be more cytotoxic and persistent than naturally occurring sphingoid bases using HT29 cells, a colon cancer cell line. Although the molecular targets of sphingoid bases are not well delineated, Enigmol shared one of the mechanisms that has been found for naturally occurring sphingoid bases: normalization of the aberrant accumulation of β-catenin in the nucleus and cytoplasm of colon cancer cells due to defect(s) in the adenomatous polyposis coli (APC)/β-catenin regulatory system. Enigmol also had antitumor efficacy when administered orally to Min mice, a mouse model with a truncated APC gene product (C57Bl/6J(Min/+) mice), decreasing the number of intestinal tumors by half at 0.025% of the diet (w/w), with no evidence of host toxicity until higher dosages. Enigmol was also tested against the prostate cancer cell lines DU145 and PC-3 in nude mouse xenografts and suppressed tumor growth in both. Thus, Enigmol represents a novel category of sphingoid base analogue that is orally bioavailable and has the potential to be effective against multiple types of cancer.
authors.affiliation: School of Biology, 310 Ferst Drive, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Symolon
authors.forename: Anatoliy
authors.initials: A
authors.lastname: Bushnev
authors.forename: Qiong
authors.initials: Q
authors.lastname: Peng
authors.forename: Harsha
authors.initials: H
authors.lastname: Ramaraju
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Mays
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Pruett
authors.forename: M Cameron
authors.initials: MC
authors.lastname: Sullards
authors.forename: Dirck L
authors.initials: DL
authors.lastname: Dillehay
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015394:Molecular Structure; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013107:Sphingolipids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: C559817:2-amino-3,5-dihydroxyoctadecane; D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D013107:Sphingolipids; D051176:beta Catenin; D013110:Sphingosine