Enhancement of the activity of doxorubicin by inhibition of glutamate transporter
Abstract
Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasing 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 suppression of the glutamate transporter in tumor 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 concentration of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 cells, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected 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.
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Theanine inhibits efflux of chemotherapeutic agents such as doxorubicin, idarubicin, cisplatin, and irinotecan, causing them to accumulate in tumor cells and protecting normal cells through antioxidant property and maintenance of cellular GSH.
“The efflux of chemotherapeutic agents (e.g.doxorubicin, idarubicin, cisplatin, irinotecan) are inhibited by theanine, which causes them to accumulate in tumor cells and to protect normal cells from damage by these drugs through its antioxidant property and maintaining cellular GSH level [22,[27][28][29] .”
From l -theanine: A potential multifaceted natural bioactive amide as health supplement (2017) · cites this paper as [27]
L-theanine competitively inhibits glutamate transport into infected tumor cells and can decrease intracellular glutathione levels.
“L-theanine, as chemotherapeutic agent, competitively inhibits glutamate transport into the infected tumor cells, can also decrease intracellular glutathione (GSH) levels.”
From l -theanine: A potential multifaceted natural bioactive amide as health supplement (2017) · cites this paper as [27]
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References 26 · Cited by 52
- Authors
- Sadzuka, Y., Sugiyama, T., Suzuki, T., & Sonobe, T.
- Affiliations
- Shizuoka University (JP)
- Meiji Pharmaceutical University (JP)
- Corresponding author
- Sadzuka, Yasuyuki
- ORCID
- Suzuki, Toshihiro
- Venue
- Toxicology Letters
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 123
- Issue
- 2-3
- Pages
- 159-167
- ISSN
- 0378-4274 (ISSN-L)
- OpenAlex
- W2089090098
- Cited by
- 52
- References
- 26
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2013: 2 · 2012: 5
- FWCI
- 1.62
- 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 › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- doxorubicin, theanine, MRP5, drug efflux, glutamate, glutathione, anticancer activity
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Biological Transport, Dose-Response Relationship, Drug, Doxorubicin, Drug Screening Assays, Antitumor, Female, Glutamates, Glutathione, Ketoprofen, Male, Mice, Inbred C57BL, Neoplasm Transplantation, Neoplasms, Experimental, RNA, Messenger, Sodium, Temperature, Tumor Cells, Cultured, Glutamic Acid, Buthionine Sulfoximine, Amino Acid Transport System X-AG, ATP-Binding Cassette, Sub-Family C Proteins, Mice
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