The potential of epigallocatechin gallate in the chemoprevention and therapy of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), one of the most notorious malignancies globally, has a high fatality and poor prognosis. Though remarkable breakthroughs have been made in the therapeutic strategies recently, the overall survival of HCC remains unsatisfactory. Consequently, the therapy of HCC remains a great challenge. Epigallocatechin gallate (EGCG), a natural polyphenol extracted from the leaves of the tea bush, has been extensively investigated for its antitumor effects. In this review, we summarize the previous literature to elucidate the roles of EGCG in the chemoprophylaxis and therapy of HCC. Accumulating evidence has confirmed EGCG prevents and inhibits the hepatic tumorigenesis and progression through multiple biological mechanisms, mainly involving hepatitis virus infection, oxidative stress, proliferation, invasion, migration, angiogenesis, apoptosis, autophagy, and tumor metabolism. Furthermore, EGCG enhances the efficacy and sensitivity of chemotherapy, radiotherapy, and targeted therapy in HCC. In conclusion, preclinical studies have confirmed the potential of EGCG for chemoprevention and therapy of HCC under multifarious experimental models and conditions. Nevertheless, there is an urgent need to explore the safety and efficacy of EGCG in the clinical practice of HCC.

The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy

“…Therefore, targeting VEGF/VEGFR signaling has become a major treatment option for many cancers. A compelling body of evidence revealed EGCG can downregulate the expression levels of VEGF by inhibiting multiple tumor-related signaling molecules, such as PI3K, Akt, mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1alpha (HIF-1α), NF-κB, and STAT3, thus inhibiting endothelial angiogenesis and tumor progression ( 16 , 86 , 141 – 143 ). Furthermore, studies confirmed EGCG significantly reduced basic fibroblast growth factor (bFGF) levels in ECs and tumor cells, by increasing bFGF ubiquitination and 20S proteasome activity, which led to bFGF degradation ( 144 , 145 ).…”

“…Relevant evidence has revealed the transcriptional programs of these transporters are largely regulated by HIF-1α, ATF4, and Myc ( 198 , 199 ). Indeed, it has been observed that EGCG can markedly reduce the expression of these transcription factors in tumors ( 16 , 200 , 201 ). Given that, we speculate EGCG may downregulate the expression levels of the abovementioned glutamine receptors, but direct experimental results are still needed to confirm our hypothesis.…”

“…Although abundant preclinical and clinical studies have confirmed the therapeutic potential of EGCG on tumors, it is undeniable that the oral bioavailability of EGCG is relatively low, which is an important stumbling block limiting its further clinical application ( 23 ). The possible reasons are that EGCG is mainly absorbed by passive diffusion, is prone to instability in alkaline intestinal fluid, and may be subject to catabolism by intestinal microorganisms, which may significantly affect its bioavailability ( 16 , 17 ). Therefore, the development of liposomal encapsulation or nanomodification is conducive to ameliorating its stability and biological availability and achieving clinical efficacy beyond expectations.…”

“…In addition, the scientific community currently generally agrees drinking tea is fairly appropriate for humans, as there are few reports of serious adverse events from drinking tea ( 15 ). Generally, according to the difference in the degree of fermentation, tea can be classified into 6 categories: green, white, yellow, oolong, black, and dark teas, among which, green tea is made from the fresh leaves of tea bushes through the process of blanching, rolling, and drying, without specific fermentation, so a large number of catechins are retained ( 15 , 16 ). Catechins are the foremost polyphenolic substances in green tea, mainly including epigallocatechin gallate (EGCG), epigallocatechin, epicatechin gallate, gallocatechin gallate, epicatechin, and gallocatechin, among which EGCG is the most abundant catechin in green tea ( 13 , 16 ).…”

“…Additionally, EGCG can regulate DNA methylation and histone acetylation levels through interacting with DNA methyltransferases and histone deacetylases to epigenetically control tumor genome expression ( 22 ). Furthermore, evidence has revealed that EGCG remarkably overcomes chemotherapy resistance and re-sensitizes tumor cells to multiple chemotherapy drugs, such as cisplatin, 5-fluorouracil, doxorubicin, and daunorubicin ( 16 , 23 ). Nevertheless, its regulatory roles and relevant mechanisms in TME, metabolic reprogramming, and cancer immunotherapy remain obscure and need to be further elucidated and discussed.…”