L-type amino acid transporter 1 inhibitors inhibit tumor cell growth

Cancer Sci. 2010 Jan;101(1):173-9. doi: 10.1111/j.1349-7006.2009.01386.x. Epub 2009 Oct 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / analysis
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzoxazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Fusion Regulatory Protein 1, Light Chains / analysis
  • HT29 Cells
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Large Neutral Amino Acid-Transporter 1 / physiology*
  • Leucine / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases
  • Tyrosine / analogs & derivatives*
  • Tyrosine / pharmacology
  • Xenograft Model Antitumor Assays


  • 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid
  • Amino Acid Transport System y+
  • Antineoplastic Agents
  • Benzoxazoles
  • Fusion Regulatory Protein 1, Light Chains
  • Intracellular Signaling Peptides and Proteins
  • Large Neutral Amino Acid-Transporter 1
  • SLC7A8 protein, human
  • Tyrosine
  • MTOR protein, human
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Leucine