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

Koji Oda1, Noriko Hosoda, Hiroshi Endo

  • 1Tanabe R&D Co, Ltd, Toda, Saitama, Japan.

Cancer Science
|November 11, 2009
PubMed

Insights

A novel compound, KYT-0353, selectively inhibits L-type amino acid transporter 1 (LAT1) in cancer cells. This LAT1 inhibitor demonstrated significant anti-tumor effects in vitro and in vivo, showing potential as a new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • L-type amino acid transporter 1 (LAT1) is overexpressed on tumor cell membranes, unlike LAT2 on normal cells.
  • Selective LAT1 inhibitors represent a novel molecular target for cancer therapy.
  • KYT-0353 is a novel compound identified with high in vitro LAT1 selectivity.

Purpose of the Study:

  • To evaluate the efficacy of KYT-0353 as a potential anti-tumor agent.
  • To assess the in vitro and in vivo effects of KYT-0353 on cancer cells and tumors.
  • To investigate the safety profile of KYT-0353 in preclinical models.

Main Methods:

  • Assessed inhibition of (14)C-leucine uptake and cell growth in HT-29 colon cancer cells and mouse renal proximal tubule cells.
  • Determined IC(50) values for KYT-0353 in cellular assays.
  • Evaluated in vivo anti-tumor efficacy and body weight changes in nude mice bearing HT-29 tumors after intravenous administration of KYT-0353.

Main Results:

  • KYT-0353 significantly inhibited (14)C-leucine uptake and cell growth in HT-29 cells (IC(50)s: 0.06 µM and 4.1 µM, respectively).
  • KYT-0353 also inhibited uptake and growth in LAT1-expressing mouse renal cells (IC(50)s: 0.14 µM and 16.4 µM, respectively).
  • Intravenous KYT-0353 demonstrated significant dose-dependent inhibition of HT-29 tumor growth in mice (up to 77.2% inhibition) with minimal body weight depression.

Conclusions:

  • KYT-0353 exhibits potent anti-tumor activity against colon cancer cells in vitro and in vivo.
  • The compound's efficacy is likely mediated by selective inhibition of LAT1.
  • KYT-0353 shows promise as a novel anti-cancer therapeutic agent with a favorable preliminary safety profile.

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