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: Koji Oda, Noriko Hosoda, Hiroshi Endo, Kunio Saito, Kenji Tsujihara, Michio Yamamura, Takeshi Sakata, Naohiko Anzai, Michael F Wempe, Yoshikatsu Kanai, Hitoshi Endou
• Journal: Cancer science (Cancer Sci) Vol. 101 Issue 1 Pg. 173-9 (Jan 2010) ISSN: 1349-7006 [Electronic] England
• PMID: 19900191 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, pharmacology)
• Xenograft Model Antitumor Assays