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Tumor Biology

, Volume 37, Issue 7, pp 8555–8566 | Cite as

The green tea polyphenol EGCG potentiates the antiproliferative activity of sunitinib in human cancer cells

Original Article

Abstract

Sunitinib is a promising drug for clinical applications; however, the efficacy is reduced by the feedback activation of many signaling cascades. In this study, we investigated the ability of (−)-epigallocatechin-3-gallate (EGCG) to synergize with sunitinib and inhibit insulin receptor substrate (IRS)/mitogen-activated protein kinase (MAPK) pathway activation. MCF-7, H460, and H1975 cell lines with PIK3CA mutations were treated with sunitinib or mock treated 0–24 h and then pulsed with 0–50 μM EGCG for another 12 h; cell proliferation and vascular endothelial growth factor (VEGF) secretion were then evaluated. To analyze angiogenesis and VEGF levels in vivo, MCF-7 and H460 xenograft tumors were established. Cell growth signaling cascades were assessed via western blotting in vitro, and tumors were subjected to immunohistochemical analyses to evaluate signaling cascades in vivo. EGCG enhanced the antiproliferation and VEGF secretion-reducing effects of sunitinib in the three tested cell lines. In vivo, EGCG administration at 4 h after sunitinib treatment resulted in greater tumor shrinkage and antiangiogenesis than with sunitinib alone. We further demonstrated that sunitinib exposure induces insulin receptor substrate-1 (IRS-1) upregulation and activation of MAPK signaling. More strikingly, EGCG treatment downregulated IRS-1 levels and suppressed mitogenic effects. In vivo, immunohistochemical analyses demonstrated marked suppression of the IRS/MAPK/p-S6K1 signaling cascade by EGCG, especially after sunitinib treatment. EGCG potentially synergizes with sunitinib due to its ability to suppress the IRS/MAPK signaling induced by sunitinib. We conclude that administration of EGCG after sunitinib treatment represents a promising strategy for the treatment of cancer.

Keywords

Catechin Pyrroles Feedback MAP kinase signaling system Insulin receptor substrate proteins 

Abbreviations

NS

0.9 % NaCl solution

DMEM

Dulbecco’s modified Eagle’s medium

MTT

3-(4,5-Dimethyl-thiazol-2-yl)-2,5- diphenyl

EGCG

((−)-Epigallocatechin-3-gallate)

mTOR

Mammalian target of rapamycin

PI3K

Phosphoinositide 3-kinase

p70S6K

p70S6 kinase

MAPK

Mitogen-activated protein kinase

IRS-1

Insulin receptor substrate-1

CI

Combination index

MVD

Micro-vessel density

VEGFr

Vascular endothelial growth factor receptor

TKI

Tyrosine kinase inhibitor

ELISA

Enzyme-linked immunosorbent assay

MTT

3-(4,5-Dimethyl-thiazol-2-yl)-2,5- diphenyl

FBS

Fetal bovine serum, complete medium

HIF-1α

Hypoxia-inducible factor-1α

IGF-IR

Insulin-like growth factor I receptor

Notes

Acknowledgments

The present study was supported by the Project of the National Natural Science Foundation of China (no. 81272457). I am indebted to Jie Zhang and Yan-Jun Wen for their technical help.

Authors’ contributions

Yi Zhou and Jie Tang carried out the molecular genetic studies and participated in drafting the manuscript. Yi Zhou, Jing Ding, Zhi-Ke Li, Ye Chen, Ke Cheng, and Cong Li carried out the immunoassays. Yi Zhou and Ji-Yan Liu participated in the design of the study and performed the statistical analysis. Yi Zhou and Ji-Yan Liu conceived of the study and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Yi Zhou
    • 1
  • Jie Tang
    • 1
  • Yang Du
    • 1
  • Jing Ding
    • 1
  • Ji-Yan Liu
    • 1
  1. 1.Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Medical SchoolWest China Hospital, Sichuan UniversityChengduChina

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