Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo

Abstract

BackgroundEpigallocatechin-3-gallate (EGCG), one of the major catechins in green tea, is a potential chemopreventive agent for various cancers. The aim of this study was to examine the effect of EGCG on the expression of heat shock proteins (HSPs) and tumor suppression.MethodsCell colony formation was evaluated by a soft agar assay. Transcriptional activity of HSP70 and HSP90 was determined by luciferase reporter assay. An EGCG-HSPs complex was prepared using EGCG attached to the cyanogen bromide (CNBr)-activated Sepharose 4B. In vivo effect of EGCG on tumor growth was examined in a xenograft model.ResultsTreatment with EGCG decreased cell proliferation and colony formation of MCF-7 human breast cancer cells. EGCG specifically inhibited the expression of HSP70 and HSP90 by inhibiting the promoter activity of HSP70 and HSP90. Pretreatment with EGCG increased the stress sensitivity of MCF-7 cells upon heat shock (44°C for 1 h) or oxidative stress (H2O2, 500 μM for 24 h). Moreover, treatment with EGCG (10 mg/kg) in a xenograft model resulted in delayed tumor incidence and reduced tumor size, as well as the inhibition of HSP70 and HSP90 expression.ConclusionsOverall, these findings demonstrate that HSP70 and HSP90 are potent molecular targets of EGCG and suggest EGCG as a drug candidate for the treatment of human cancer.

High-dose green tea polyphenols induce nephrotoxicity in dextran sulfate sodium-induced colitis mice by down-regulation of antioxidant enzymes and heat-shock protein expressions

“…6d). These results are consistent with those of Tran et al, who previously found that HSP90 was repressed by EGCG in MCF-7 human breast cancer cells (Li et al 2009;Tran et al 2010). Because HSP90 is the most abundant molecular chaperone and plays pivotal roles in maintaining organ homeostasis (Shi et al 2007;Hackl et al 2010), its down-regulation by GTPs might be associated with organ dysfunction and toxicity.…”

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data

“…Besides known natural and synthetic agents, a number of different bioactive food components, such as quercitin (Aalinkeel et al 2008), genistein (Basak et al 2008), and epigallocatechin-3-gallate (Tran et al 2010), were also identified as potent HSP90 inhibitors. Modulation of post-translational mechanisms is an important approach to interfere with the regulation of HSP90.…”

Pharmacokinetic-Pharmacodynamic Modeling of Biomarker Response and Tumor Growth Inhibition to an Orally Available Heat Shock Protein 90 Inhibitor in a Human Tumor Xenograft Mouse Model

“…However, little detailed investigation of PKPD relationships of HSP90 inhibitors to their effects on downstream biomarkers and antitumor efficacy has been published to date. Reported PKPD results were limited largely to simple demonstrations of dose-dependent inhibition of HSP90 client proteins and/or tumor growth inhibition in human tumor xenograft models (Banerji et al, 2005;Massey et al, 2010;Oude Munnink et al, 2010;Sun et al, 2010;Tran et al, 2010). There was one notable study (Xu et al, 2003) showing physiologically based PKPD modeling of 17-AAG and its metabolite for biomarkers in tumor-bearing mice, but a relationship between the inhibitor concentrations or biomarkers versus antitumor efficacy was not addressed.…”