Enigmol: A Novel Sphingolipid Analogue with Anticancer Activity against Cancer Cell Lines and In vivo Models for Intestinal and Prostate Cancer

• Type of Material: Article
• Authors: Holly Symolon, Emory University; Anatoliy Bushnev, Emory University; Qiong Peng, Georgia Institute of Technology; Harsha Ramaraju, Emory University; Suzanne G. Mays, Emory University; Jeremy C. Allegood, Georgia Institute of Technology; Sarah T. Pruett, Emory University; M. Cameron Sullards, Georgia Institute of Technology; Dirck L. Dillehay, Emory University; Dennis Liotta, Emory University; Alfred H. Merrill, Georgia Institute of Technology
• Language: English
• Date: 2011-04
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2011 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-10-0754
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• ISSN: 1535-7163
• Volume: 10
• Issue: 4
• Start Page: 648
• End Page: 657
• Grant/Funding Information: Grant Support: NIH grant U19-CA87525 (all authors) and funds from the Smithgall Institute Chair in Molecular and Cell Biology at Georgia Tech (A. Merrill).
• Keywords: Colon cancer; Min mouse; Prostate cancer; Analogs; Metabolism; Sphingolipids
• Research Categories: Chemistry, Biochemistry; Health Sciences, Oncology; Biology, Cell

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 analog, (2S,3S,5S)-2-amino-3,5-dihydroxyoctadecane (“Enigmol”), that cannot be phosphorylated by sphingosine kinases and is slowly N-acylated, therefore, is more persistent than natural sphingoid bases. Enigmol had potential anti-cancer 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: to “normalize” 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 anti-tumor efficacy when administered orally to Min mice, a mouse model with a truncated APC gene product (C57Bl/6JMin/+ 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 analog that is orally bioavailable and has the potential to be effective against multiple types of cancer.