l-Type amino acid transporter 1 inhibitors inhibit tumor cell growth

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 ¹⁴C-leucine uptake and cell growth in human colon cancer-derived HT-29 cells; IC₅₀s were 0.06 μ m and 4.1 μ m , respectively. KYT-0353 also inhibited ¹⁴C-leucine uptake in mouse renal proximal tubule cells expressing l- type amino acid transporter 1, and inhibited cell growth; IC₅₀s 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)