Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin.
Theanine, a major amino acid existing in green tea, enhanced the antitumor activity of doxorubicin (DOX) due to inhibition of DOX efflux from tumor cells. In order to clarify the mechanism, we have investigated the contribution of glutamate transporters to the action of theanine, because theanine is a glutamate analogue. In M5076 ovarian sarcoma cells, glutamate transport inhibitors reduced the efflux of DOX, as well as theanine. Incidentally, theanine significantly inhibited the glutamate uptake by M5076 cells in a concentration-dependent manner similar to specific inhibitors. These results suggested that the inhibition of DOX efflux was induced by the inhibition of glutamate transport by theanine. In addition, RT-PCR and Western blot analysis revealed the expression of GLAST and GLT-1, astrocytic high-affinity glutamate transporters, in M5076 cells. Thus, theanine was shown to competitively inhibit the glutamate uptake by acting on these glutamate transporters. This action suggested the contribution of glutamate transporters to the inhibition of DOX efflux by theanine. We revealed the novel mechanism of enhancement of the antitumor efficacy of DOX via the inhibition of glutamate transporters by theanine.
Sugiyama
T
T
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, 422-8526, Shizuoka, Japan.
Sadzuka
Y
Y
Tanaka
K
K
Sonobe
T
T
D015074:2-Aminoadipic Acid / Q000494:pharmacology; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D027322:Amino Acid Transport System X-AG; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002250:Carbon Radioisotopes; D002462:Cell Membrane / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D005971:Glutamates; D015074:2-Aminoadipic Acid; D018698:Glutamic Acid; C020889:dihydrokainic acid; D004317:Doxorubicin; C026166:theanine; D007608:Kainic Acid