RRC ID 65616
Author Satonaka H, Ishida K, Takai M, Koide R, Shigemasa R, Ueyama J, Ishikawa T, Hayashi K, Goto H, Wakusawa S.
Title (-)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Through the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways.
Journal Anticancer Res
Abstract BACKGROUND/AIM:(-)-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.
MATERIALS AND METHODS:Rhodamine 123 (Rho123) was used for P-gp substrate. Western blotting and polymerase chain reactions (PCRs) were conducted using specific antibodies and primer sets.
RESULTS: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.
CONCLUSION:EGCG inhibited DOX-induced overexpression of P-gp through the coordinate inhibitory action on MEK/ERK and PI3K/Akt signaling pathways.
Volume 37(11)
Pages 6071-6077
Published 2017-11-1
DOI 10.21873/anticanres.12055
PII 37/11/6071
PMID 29061787
MeSH ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors ATP Binding Cassette Transporter, Subfamily B / genetics ATP Binding Cassette Transporter, Subfamily B / metabolism Antibiotics, Antineoplastic / pharmacology Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Catechin / analogs & derivatives* Catechin / pharmacology Doxorubicin / pharmacology* Gene Expression Regulation, Neoplastic / drug effects* Humans Liver Neoplasms / drug therapy Liver Neoplasms / metabolism Liver Neoplasms / pathology MAP Kinase Signaling System / drug effects* Neuroprotective Agents / pharmacology Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors* Phosphorylation / drug effects Proto-Oncogene Proteins c-akt / antagonists & inhibitors* Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Rhodamine 123 / metabolism Signal Transduction Tumor Cells, Cultured
IF 1.994
Human and Animal Cells Hep G2