(–)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Τhrough the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways
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説明
(-)-Epigallocatechin-3-gallate (EGCG) has been indicated to regulate the function of P-glycoprotein (P-gp), which is a drug transporter encoded by the MDR1 (ABCB1) gene. P-gp expression is induced by doxorubicin (DOX). We aimed to clarify the mechanisms and inhibitory effects of EGCG on DOX-induced P-gp expression in HepG2 cells.Rhodamine 123 (Rho123) was used for P-gp substrate. Western blotting and polymerase chain reactions (PCRs) were conducted using specific antibodies and primer sets.The DOX-pretreated cells accumulated a significantly decreased amount of Rho123), than control cells; however, the cells pretreated with EGCG and DOX, in combination, accumulated Rho123 more than DOX-pretreated cells. DOX induced the overexpression of MDR1 mRNA and increased the phosphorylation of Akt, ERK1/2, p38 MAPK and JNK. EGCG significantly inhibited the phosphorylation of Akt and ERK. The DOX-induced P-gp overexpression was partially suppressed by an inhibitor of MEK1/2 (U0126), but not by a PI3K inhibitor (LY294002). Interestingly, the expression of P-gp was synergistically inhibited by combined treatment of U0126 with LY294002 and also inhibited by an mTORC1 inhibitor, rapamycin.EGCG inhibited DOX-induced overexpression of P-gp through the coordinate inhibitory action on MEK/ERK and PI3K/Akt signaling pathways.
収録刊行物
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- Anticancer Research
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Anticancer Research 37 2017-10-23
Anticancer Research USA Inc.
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キーワード
- ATP Binding Cassette Transporter, Subfamily B
- Antibiotics, Antineoplastic
- Carcinoma, Hepatocellular
- MAP Kinase Signaling System
- Liver Neoplasms
- Catechin
- Gene Expression Regulation, Neoplastic
- Phosphatidylinositol 3-Kinases
- Neuroprotective Agents
- Doxorubicin
- Tumor Cells, Cultured
- Humans
- Rhodamine 123
- Phosphorylation
- Proto-Oncogene Proteins c-akt
- Phosphoinositide-3 Kinase Inhibitors
- Signal Transduction