Therapeutic potential of a novel prodrug of green tea extract in induction of apoptosis via ERK/JNK and Akt signaling pathway in human endometrial cancer

Abstract

Background Previous studies have shown a major green tea polyphenol (−)-epigallocatechin-3-gallate ((−)-EGCG) as a powerful anti-cancer agent. However, its poor bioavailability and requirement of a high dosage to manifest activity have restricted its clinical application. Recently, our team synthesized a peracetate-protected derivative of EGCG, which can act as a prodrug of (−)-EGCG (ProEGCG) with enhanced stability and improved bioavailability in vitro and in vivo. Herein, we tested the therapeutic efficacy of this novel ProEGCG, in comparison to EGCG, toward human endometrial cancer (EC). Methods In this study, the effects of ProEGCG and EGCG treatments on cell growth, cell survival and modulation of intracellular signaling pathways in RL95–2 and AN3 CA EC cells were compared. The antiproliferative effect was evaluated by cell viability assay. Apoptosis was measured by annexin/propidium iodide staining. Expression of mitogen-activated protein kinases, markers of proliferation and apoptosis were measured by immunoblot analysis. In addition, the effects of ProEGCG and EGCG on tumor growth, vessel formation and gene expression profiles on xenograft models of the EC cells were investigated. Results We found that treatment with ProEGCG, but not EGCG, inhibited, in a time- and dose-dependent manner, the proliferation and increased apoptosis of EC cells. Treatment with low-dose ProEGCG significantly enhanced phosphorylation of JNK and p38 MAPK and inhibited phosphorylation of Akt and ERK which are critical mediators of apoptosis. ProEGCG, but not EGCG, elicited a significant decrease in the growth of the EC xenografts, promoted apoptotic activity of tumour cells in the EC xenografts, and decreased microvessel formation, by differentially suppressing anti-apoptotic molecules, NOD1 and NAIP. Notably, no obvious adverse effects were detected. Conclusions Taken together, ProEGCG at a low dose exhibited anticancer activity in EC cells through its anti-proliferative, pro-apoptotic and anti-tumor actions on endometrial cancer in vitro and in vivo. In contrast, a low dose of EGCG did not bring about similar effects. Importantly, our data demonstrated the efficacy and safety of ProEGCG which manifests the potential of a novel anticancer agent for the management of endometrial cancer.

A Narrative Review of the Role of Diet and Lifestyle Factors in the Development and Prevention of Endometrial Cancer

“…Interest in this has expanded and a meta-analysis of 7 published studies reported that the protective effect of green tea was better than that of black tea and that a 25% decrease in EC risk could be achieved by drinking an additional 2 cups of green tea per day [ 316 ] ( Table 4 ). More recent evidence using a xenograft model indicated that the use of a prodrug form of EGCG inhibited tumour cell proliferation and increased apoptosis in a time- and dose-dependent manner [ 317 ]. One effect was that microvessel formation was decreased, thereby reducing blood flow to the xenograft.…”

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

“…In response to EGCG treatment, the observed reduction in ERK1/2 phosphorylation in colon, pancreatic and lung cancer cells was found to promote the expression of the Bcl‐2 family of apoptotic proteins [107]. ProEGCG, a derivative of EGCG, significantly reduced the phosphorylation of ERK and Akt in endometrial cancer cells, suggesting that the PI3K/Akt/mTOR and MAPK signaling pathways play an important function in the apoptotic pathway [108]. In addition, an inhibitory phosphorylation of the Akt signaling pathway has been discovered to be a potential EGCG mechanism underlying the induction of apoptosis in HCC and colon cancer cells [45,47].…”

Risk factors of endometrial cancer in patients with endometrial hyperplasia: implication for clinical treatments

“…The results of this study also suggest that severe EH is also a high-risk factor for EC. However, the clinical reason for the failure to find coexisting EC before surgery may be that the preoperative endometrial sampling is mainly by diagnosing curettage, AEH lesions may be single or scattered lesions, which are affected by the experience of the surgeon, and there is a possibility of missed curettage [35,36]. In addition, the diagnosis of well-differentiated EC is mainly based on the presence or absence of endometrial stroma, but it is sometimes difficult to determine [37].…”