Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo.

Autor:	Chen B; Department of Chemistry, Université de Montréal , P.O. Box 6128, Station Centre-Ville, Montréal, Quebec H3C 3J7, Canada., Roy SG; Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States., McMonigle RJ; Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States., Keebaugh A; Community & Environmental Medicine, University of California , Irvine, FRF 100, California 92697-1825, United States., McCracken AN; Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States., Selwan E; Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States., Fransson R; Department of Chemistry, Université de Montréal , P.O. Box 6128, Station Centre-Ville, Montréal, Quebec H3C 3J7, Canada., Fallegger D; Institute of Pharmacology, University of Bern , Inselspital INO-F, CH-3010 Bern, Switzerland., Huwiler A; Institute of Pharmacology, University of Bern , Inselspital INO-F, CH-3010 Bern, Switzerland., Kleinman MT; Community & Environmental Medicine, University of California , Irvine, FRF 100, California 92697-1825, United States., Edinger AL; Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States., Hanessian S; Department of Chemistry, Université de Montréal , P.O. Box 6128, Station Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2016 Feb 19; Vol. 11 (2), pp. 409-14. Date of Electronic Publication: 2015 Dec 14.
DOI:	10.1021/acschembio.5b00761
Abstrakt:	FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anticancer agent in multiple animal models. Our published work indicates that the anticancer effects of FTY720 do not depend on actions at S1P receptors but instead stem from FTY720s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here, we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients.
Databáze:	MEDLINE
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