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Abstract. Background/Aim: (-)-Epigallocatechin-3-gallate (EGCG) has been indicated to regulate the function of Pglycoprotein (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 DOXpretreated 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.(-)-Epigallocatechin gallate (EGCG) is the most abundant component of tea polyphenols having various profitable properties, including anti-oxidative activity and cancerpreventive effect (1). In addition, concerning antitumor drug resistance, EGCG has been shown to decrease doxorubicin (DOX) resistance in a human carcinoma xenograft model mice (2) and inhibit the transport function of P-glycoprotein (P-gp), an export drug transporter causing antitumor multidrug resistance (MDR) in tumor cells (3)(4)(5).Human P-gp is a plasma membrane protein of 170 kDa encoded by the MDR1 (ABCB1) gene. The expression of MDR1 gene and P-gp is affected by various chemical substances and physico-chemical stress (5-7). We have previously suggested that the P-gp level was up-regulated through the activation of protein kinase C/nuclear factor-ĸB (PKC/NF-ĸB) in rats with streptozotocin-induced diabetes (8). Further, the expression of MDR1 gene has been also shown to be induced by PI3K/Akt/NF-ĸB signaling (9,10).EGCG has been shown to activate ERK and PI3K/Akt signaling and induce antioxidant enzymes in human mammary epithelial cells (11). Contrarily, it has been shown that EGCG inhibits the PI3K/Akt system in fibroblast cells (12) and the phosphorylation of ERK and Akt kinases in epidermal growth factor (EGF)-stimulated cells (13). More recently, accumulating evidence indicates that EGCG can inhibit PI3K/Akt and MAPK signaling systems (14)(15)(16)(17).From these backgrounds, in the present study, we aimed to clarify whether EGCG could suppress MDR and inhibit the induction of P-gp overexpression by DOX through inhibition of PI3K/Akt and ERK/MAPK signal transduction s...