Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin

Toxicology Letters
T SugiyamaT Sonobe

Abstract

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.

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Citations

Mar 13, 2002·Cancer Letters·Yasuyuki SadzukaTakashi Sonobe
Feb 22, 2003·Biochimica Et Biophysica Acta·Haruhito TsugeTomonori Unno
Dec 4, 2003·Biochimica Et Biophysica Acta·Tomomi Sugiyama, Yasuyuki Sadzuka
Sep 1, 2005·The Journal of Alternative and Complementary Medicine : Research on Paradigm, Practice, and Policy·Raymond CooperDorothy M Morré
Sep 6, 2005·Biological & Pharmaceutical Bulletin·Yasuyuki SadzukaTakashi Sonobe
Nov 21, 2002·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Yasuyuki SadzukaTakashi Sonobe
Mar 4, 2014·Biological & Pharmaceutical Bulletin·Michiko Miyashita, Yasuyuki Sadzuka
Dec 7, 2007·International Journal of Pharmaceutics·Yasuyuki SadzukaTakashi Sonobe
Jan 24, 2007·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Yasuyuki Sadzuka, Takashi Sonobe
Jun 9, 2006·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·J F BorzellecaW Hall
Sep 6, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Yasuyuki SadzukaTakashi Sonobe
Dec 12, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Michiko Miyashita, Yasuyuki Sadzuka
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Apr 28, 2009·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jovanka KolarovicLjiljana Gvozdenovic
Nov 29, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hui YangLei Xue
Sep 30, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jovanka KolarovicMatilda Vojnovic
Dec 24, 2005·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·Gregory Eschenauer, Burgunda V Sweet
Aug 25, 2020·Journal of Biochemical and Molecular Toxicology·Fatemeh YarmohammadiGholamreza Karimi
Sep 8, 2009·International Journal of Pharmaceutics·Yasuyuki SadzukaTakashi Sonobe

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