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

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.

Therapeutic effects of EGCG: a patent review

“…NF-kB, its components and AP1 are the potential targets for EGCG cancer prevention [15]. EGCG was shown to enhance the antiproliferative role of sunitinib, an anticancer drug, by downregulating MAPK pathway [31]. Katiyar et al reported that treating normal human epidermal keratinocytes (NHEK) to UVB radiation induces the release of hydrogen peroxide due to oxidative stress.…”

“…Combination of EGCG with Sunitinib, a FDA approved drug for cancer treatment, down regulates MAPK signaling in human cancer cells. Also, it leads to greater tumor shrinkage and anti-angiogenesis in vivo as compared to sunitinib alone [31]. EGCG in combination with cisplatin has also demonstrated promising anticancerous effect on cell line [23].…”

Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer

“…EGCG inhibits human prostate cancer cell (PC-3) proliferation by PI3-K-dependent signalling pathway [54]. In colon cancer EGCG induces the activation of mitogen-activated protein kinase (MAPK) [55] and Akt pathways [56]. In silico modelling approaches reveals that EGCG physically interacts with the ligand-binding domain of androgen receptor that is overexpressed in prostate cancer, leading to the inhibition of cell growth [57].…”

Prevention of Breast Cancer by Natural Phytochemicals: Focusing on Molecular Targets and Combinational Strategy

“…Recently, Scandlyn's research group has also used ER‐negative breast cancer cells to confirm that EGCG + tamoxifen/raloxifene elicited synergistic cytotoxicity and earlier enhanced apoptotic response in MDA‐MB‐231 cells, which correlated with a decrease in CYP1B1 expression and the blockage of epidermal growth factor receptor (EGFR) and mTOR signaling . Moreover, EGCG potentially synergizes with sunitinib to exert greater growth‐inhibitory effects due to its ability to suppress the insulin receptor substrate‐1 (IRS‐1)/extracellular‐signal‐regulated kinase (ERK) signaling induced by sunitinib . Collectively, evidences support approaches to augment apoptotic mechanism by targeting the pro‐survival, redox, autophagy, MDR, and epigenetic signaling pathways as rational therapeutic strategies to combat or delay the onset of chemoresistance and radioresistance in breast cancer.…”