System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line.
LAT1, a subunit of heterodimeric system L transporter responsible for transporting neutral amino acids into cells, has been investigated in several cancers because of its onco-fetal nature. Based on the studies of its functional inhibition, LAT1 has been proposed to be a new molecular target of a cancer therapy. We have shown here that human head and neck cancer cell line, Hep-2, expresses both LAT1 and 4F2hc, another subunit of system L transporter. An inhibitor of system L, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), inhibited leucine uptake by the cells. BCH administration or restriction of essential amino acid leucine decreased viability of Hep-2 cells. Co-administration of cisplatin with BCH reduced the viability of the cells more than either agent alone. When BCH treatment preceded cisplatin administration, reduction in Hep-2 cell viability was additive. In contrast, when BCH was given after cisplatin treatment, synergistic effect in decreasing the number of viable cells was obtained. BCH treatment decreased the phosphorylation of mTOR, p70S6K and 4EBP1, suggesting that BCH enhanced anti-tumor action of cisplatin by inhibiting mTOR pathway. This potentiation may be used to reduce cisplatin exposure to alleviate many unwanted toxicity of the drug.
Yamauchi
Kohichi
K
Department of Otolaryngology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Sakurai
Hiroyuki
H
Kimura
Toru
T
Wiriyasermkul
Pattama
P
Nagamori
Shushi
S
Kanai
Yoshikatsu
Y
Kohno
Naoyuki
N
D000598:Amino Acids, Cyclic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004357:Drug Synergism; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000187:drug effects / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D000598:Amino Acids, Cyclic; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027283:Large Neutral Amino Acid-Transporter 1; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D002945:Cisplatin