Effects of kaempferol on the mechanisms of drug resistance in the human glioblastoma cell line T98G.
Food contains components that may either increase or decrease the bioavailability of a drug. In particular, it is known that grapefruit juice and St. John's Wort induce drug interactions via an effect on the drug-metabolizing enzyme cytochrome P450 (CYP). However, interactions with membrane transporters, such as P-glycoprotein and multidrug resistance-related protein (MRP), may also influence drug bioavailability. The objective of the present study was to investigate the effects of kaempferol, a flavonoid present in food, on the cytotoxicity of anticancer drugs and the mechanisms of drug resistance in the human glioblastoma cell line T98G. Acute exposure to kaempferol inhibited the efflux of calcein, a substrate of MRP; however, chronic exposure caused no apparent effect on calcein efflux. The cytotoxicity of doxorubicin was not influenced by chronic exposure of cells to kaempferol, although that of cisplatin was significantly reduced. Multidrug resistance is often associated with increased levels of MRP1, glutathione S-transferase (GST) and activity by chronic exposure to kaempferol, although MRP2 protein levels are decreased. Accordingly, we hypothesized that the cytotoxicity of anticancer drugs that conjugate with glutathione and the substrate of MRPs may be influenced by long-term intake of drugs such as kaempferol, which are substrates of MRPs and GST.
Nakatsuma
A
A
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Kagawa, Japan. nakatsumaa@kph.bunri-u.ac.jp
Fukami
T
T
Suzuki
T
T
Furuishi
T
T
Tomono
K
K
Hidaka
S
S
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005452:Fluoresceins / Q000494:pharmacology; D018565:Food-Drug Interactions; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D044949:Kaempferols / Q000494:pharmacology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000975:Antioxidants; D005452:Fluoresceins; D005982:Glutathione Transferase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D044949:Kaempferols; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C006552:kaempferol; C007740:fluorexon; C421109:multidrug resistance-associated protein 1