title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, Université de Montréal , P.O. Box 6128, Station Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States.
authors.forename: Saurabh G
authors.initials: SG
authors.lastname: Roy
authors.affiliation: Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: McMonigle
authors.affiliation: Community & Environmental Medicine, University of California , Irvine, FRF 100, California 92697-1825, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Keebaugh
authors.affiliation: Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States.
authors.forename: Alison N
authors.initials: AN
authors.lastname: McCracken
authors.affiliation: Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Selwan
authors.affiliation: Department of Chemistry, Université de Montréal , P.O. Box 6128, Station Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fransson
authors.affiliation: Institute of Pharmacology, University of Bern , Inselspital INO-F, CH-3010 Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fallegger
authors.affiliation: Institute of Pharmacology, University of Bern , Inselspital INO-F, CH-3010 Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
authors.affiliation: Community & Environmental Medicine, University of California , Irvine, FRF 100, California 92697-1825, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kleinman
authors.affiliation: Department of Developmental and Cell Biology, University of California , Irvine, 2128 Natural Sciences 1, California 92697-2300, United States.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Edinger
authors.affiliation: Department of Chemistry, Université de Montréal , P.O. Box 6128, Station Centre-Ville, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D000068876:Fingolimod Hydrochloride / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D011759:Pyrrolidines; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride