title: L-type amino acid transporter 1 inhibitors inhibit tumor cell growth.
abstract: Most tumor cell membranes overexpress L-type amino acid transporter 1, while normal cell membranes contain l-type amino acid transporter 2; both are Na(+)-independent amino acid transporters. Therefore, compounds that selectively inhibit L-type amino acid transporter 1 offer researchers with a novel cancer molecular target. Synthetic chemistry efforts and in vitro screening have produced a variety of novel compounds possessing high in vitrol-type amino acid transporter 1 selectivity; KYT-0353 was one such compound. The present studies illustrate that KYT-0353 inhibited (14)C-leucine uptake and cell growth in human colon cancer-derived HT-29 cells; IC(50)s were 0.06 microm and 4.1 microm, respectively. KYT-0353 also inhibited (14)C-leucine uptake in mouse renal proximal tubule cells expressing l-type amino acid transporter 1, and inhibited cell growth; IC(50)s were 0.14 microm and 16.4 microm, respectively. Compared to control animals, intravenously administered KYT-0353 (12.5 mg/kg and 25.0 mg/kg) showed statistically significant growth inhibition against HT-29 tumors transplanted to nude mice with maximal inhibition ratios of 65.9% and 77.2%, respectively. Body weight increase with time--a safety indicator--was slightly depressed at 12.5 mg/kg and 25.0 mg/kg with maximal ratios of 3.7% (day 2) and 6.3% (day 11), respectively. Thus, KYT-0353 showed significant growth inhibitory effects on HT-29 cells both in vitro and in vivo, whereas it only caused a slight body weight depression. Therefore, KYT-0353 appears to have potential as a novel anti-tumor agent, presumably via selective in vivol-type amino acid transporter 1 inhibition.
authors.affiliation: Tanabe R&D Co, Ltd, Toda, Saitama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Oda
authors.forename: Noriko
authors.initials: N
authors.lastname: Hosoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Endo
authors.forename: Kunio
authors.initials: K
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsujihara
authors.forename: Michio
authors.initials: M
authors.lastname: Yamamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakata
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D027182:Amino Acid Transport System y+ / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D027301:Fusion Regulatory Protein 1, Light Chains / Q000032:analysis; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D027283:Large Neutral Amino Acid-Transporter 1 / Q000502:physiology*; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C548172:2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid; D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D027301:Fusion Regulatory Protein 1, Light Chains; D047908:Intracellular Signaling Peptides and Proteins; D027283:Large Neutral Amino Acid-Transporter 1; C420646:SLC7A8 protein, human; D014443:Tyrosine; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D007930:Leucine