EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer.

Xuemin Wang,Qing Feng,Chung S Yang,Pengqi Wang,Pan Jiang,Xuerong Wang,Goli Samimi

doi:10.1371/journal.pone.0125402

Abstract

Cisplatin is one of the first-line platinum-based chemotherapeutic agents for treatment of many types of cancer, including ovary cancer. CTR1 (copper transporter 1), a transmembrane solute carrier transporter, has previously been shown to increase the cellular uptake and sensitivity of cisplatin. It is hypothesized that increased CTR1 expression would enhance the sensitivity of cancer cells to cisplatin (cDDP). The present study demonstrates for the first time that (-)-epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells and xenograft mice. EGCG inhibits the rapid degradation of CTR1 induced by cDDP. The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to the chemotherapeutic agent. In the OVCAR3 ovarian cancer xenograft nude mice model, the combination of the lower concentration of cDDP and EGCG strongly repressed the tumor growth and exhibited protective effect on the nephrotoxicity induced by cisplatin. Overall, these findings uncover a novel chemotherapy mechanism of EGCG as an adjuvant for the treatment of ovarian cancer.

Highlights

Ovarian cancer is the seventh most common cancer in women worldwide and is one of the leading causes of mortality among gynecological malignancies [1]
EGCG enhances the sensitivity of the ovarian cancer cells to cDDP
We systematically investigated the effects of EGCG on copper transporters and the uptake and efflux of cDDP in ovary cancer cells and xenograft mice

Summary

Introduction

Ovarian cancer is the seventh most common cancer (estimated age-standardized incidence and mortality) in women worldwide and is one of the leading causes of mortality among gynecological malignancies [1]. Recent studies suggested that copper transporters are involved in copper homeostasis and regulate the cellular pharmacology and sensitivity to platinum-based agents [5, 6]. The family of copper transporters consists of copper transporters and copper transporting phosphorylated ATPase (ATP7A and ATP7B) The former includes transmembrane solute carrier transporter CTR1 (encoded by SLC31A1) and CTR2 which regulate the influx of platinum-containing agents. Several studies indicated that CTR1 is a major regulator of the efficacy of platinum drugs in vitro and in vivo [9, 10]. We investigated whether EGCG could modulate the copper transporters involved in the uptake and efflux of cDDP in vitro and in vivo. The findings provides experimental evidence for considering the application of EGCG as an adjuvant in ovarian cancer therapy

Materials and Methods

Ethics statement

Statistical methods

Results

Discussion