Cited by 47Drug Transport and Resistance MechanismsAmino Acid Enzymes and MetabolismCancer, Hypoxia, and Metabolism

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

Sugiyama, Tomomi, Sadzuka, Yasuyuki, Tanaka, Koichi, Sonobe, Takashi·2001·Toxicology Letters

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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Crossref · 10.1016/s0378-4274(01)00317-4

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Authors
Sugiyama, T., Sadzuka, Y., Tanaka, K., & Sonobe, T.
Affiliations
  • Shizuoka University (JP)
  • Tokyo Medical and Dental University (JP)
Corresponding author
Sadzuka, Yasuyuki
Venue
Toxicology Letters
Publisher
Elsevier BV
Published
2001-04
Volume
121
Issue
2
Pages
89-96
ISSN
0378-4274 (ISSN-L)
OpenAlex
W1979960367
Cited by
47
References
25
Citations by year
2024: 1 · 2020: 3 · 2017: 3 · 2016: 2 · 2014: 1 · 2013: 1 · 2012: 7
FWCI
1.47
Type
journal article
Language
en
Open access
closed
Locations
  • Toxicology Letters (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
theanine, doxorubicin, glutamate transporters, drug efflux inhibition, glutamate uptake inhibition, GLAST, GLT-1, antitumor drug efficacy, competitive inhibition
MeSH terms
Antineoplastic Agents, Carbon Radioisotopes, Cell Membrane, Doxorubicin, Drug Synergism, Enzyme Inhibitors, Glutamates, Humans, Kainic Acid, Tumor Cells, Cultured, 2-Aminoadipic Acid, ATP-Binding Cassette Transporters, Glutamic Acid, Reverse Transcriptase Polymerase Chain Reaction, Amino Acid Transport System X-AG

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