Open Accessl ‐Type amino acid transporter 1 inhibitors inhibit tumor cell growth
Author(s) -
Oda Koji,
Hosoda Noriko,
Endo Hiroshi,
Saito Kunio,
Tsujihara Kenji,
Yamamura Michio,
Sakata Takeshi,
Anzai Naohiko,
Wempe Michael F.,
Kanai Yoshikatsu,
Endou Hitoshi
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01386.x
Subject(s) - transporter , chemistry , amino acid transporter , amino acid , cell growth , pharmacology , biochemistry , cancer research , biology , gene
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 vitro l‐ 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 μ m and 4.1 μ m , 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 μ m and 16.4 μ m , 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 vivo l‐ type amino acid transporter 1 inhibition. ( Cancer Sci 2009)