Enhancement of the activity of doxorubicin by inhibition of glutamate transporter

Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasin g the concentration of DOX in the tumor through the inhibition of efflux of DOX from tumor cells. As theanine reduced the level of glutamate via suppr ession of the glutamate transporter in turnor cells, we studied the change in the intracellular concentration of glutathione (GSH) and the correlation with the GSH S-conjugate export (GS-X) pump. The reduction in the concentr ation of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 ce lls, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine aff ected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.