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

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posted on 2023-04-03, 14:24 authored by Holly Symolon, Anatoliy Bushnev, Qiong Peng, Harsha Ramaraju, Suzanne G. Mays, Jeremy C. Allegood, Sarah T. Pruett, M. Cameron Sullards, Dirck L. Dillehay, Dennis C. Liotta, Alfred H. Merrill
Supplementary Methods and Results from Enigmol: A Novel Sphingolipid Analogue with Anticancer Activity against Cancer Cell Lines and In vivo Models for Intestinal and Prostate Cancer

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ARTICLE 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/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 analogue that is orally bioavailable and has the potential to be effective against multiple types of cancer. Mol Cancer Ther; 10(4); 648–57. ©2011 AACR.

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