title: A Selective and Slowly Reversible Inhibitor of l-Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells.
abstract: The l-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is overexpressed in several types of tumors, and its inhibition can result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (1), which inhibited the uptake of LAT1 substrate, l-leucin as well as cell growth. It also significantly potentiated the efficacy of bestatin and cisplatin even at low concentrations (25 μM). Inhibition was slowly reversible, as the inhibitor was able to be detached from the cell surface and blood-brain barrier. Moreover, the inhibitor was metabolically stable and selective toward LAT1. Since the inhibitor was readily accumulated into the prostate after intraperitoneal injection to the healthy mice, this compound may be a promising agent or adjuvant especially for the treatment of prostate cancer.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Huttunen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Elena
authors.initials: E
authors.lastname: Puris
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C000619638:KMH-233; D027283:Large Neutral Amino Acid-Transporter 1; D011725:Pyridines