title: A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): a pilot study in a canine model.
abstract: L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P<0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [(3)H]l-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P<0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM.
authors: Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan.
authors: Shinya
authors: S
authors: Fukumoto
authors: Kiwamu
authors: K
authors: Hanazono
authors: Dah-Renn
authors: DR
authors: Fu
authors: Yoshifumi
authors: Y
authors: Endo
authors: Tsuyoshi
authors: T
authors: Kadosawa
authors: Hidetomo
authors: H
authors: Iwano
authors: Tsuyoshi
authors: T
authors: Uchide
mesh_terms: D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D008558:Melphalan / Q000494:pharmacology; D009362:Neoplasm Metastasis; D010865:Pilot Projects
chemical_list: D000598:Amino Acids, Cyclic; D000970:Antineoplastic Agents; D027283:Large Neutral Amino Acid-Transporter 1; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D008558:Melphalan
keywords: Dog; L-type amino acid transporter 1 (LAT1); Malignant melanoma; Oncology