[Glutamate transporter mediated increase of antitumor activity by theanine, an amino acid in green tea].
We have confirmed that theanine, a major amino acid in green tea, enhances the antitumor activity of doxorubicin (DOX) without an increase in DOX-induced side effects. We believe that the action of theanine is due to decreases in glutamate uptake via inhibition of the glutamate transporter, intracellular glutathione (GSH) synthesis, GS-DOX conjugate level, and subsequent extracellular transport of GS-DOX by the MRP5/GS-X pump. To increase the clinical usefulness of theanine, we examined its effects on the antitumor activity of cisplatin and irinotecan (CPT-11), which a known to be transported by the efflux system related to MRP. Cisplatin decreased tumor volume in M5076 tumor-bearing mice. Furthermore, the combination of theanine with cisplatin increased the decrease in tumor volume as compared with the cisplatin-alone group. Tumor volume in the CPT-11-alone group did not show a decrease, but the combination of theanine with CPT-11 significantly reduced tumor volume. The concentration of cisplatin in the tumor was significantly increased by combination with theanine, and thus we assume that it correlated with the enhancement on the antitumor activity of theanine. On the other hand, changes in drug concentrations with theanine were not observed in normal tissues, but rather it is indicated that theanine tends to reduce their concentrations. Therefore theanine enhances the antitumor activity not only of DOX but also of cisplatin or CPT-11.
Sadzuka
Yasuyuki
Y
University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. sadzuka@u-shizuoka-ken.ac.jp
Yamashita
Yasuyo
Y
Kishimoto
Shuichi
S
Fukushima
Shoji
S
Takeuchi
Yoshikazu
Y
Sonobe
Takashi
T
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003864:Depression, Chemical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005971:Glutamates / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000096:biosynthesis; D000077146:Irinotecan; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D013662:Tea; D014018:Tissue Distribution
D027322:Amino Acid Transport System X-AG; D000970:Antineoplastic Agents; D005971:Glutamates; D013662:Tea; D000077146:Irinotecan; C026166:theanine; D005978:Glutathione; D002945:Cisplatin; D002166:Camptothecin