Abstract
Decades of research have enabled us to develop a better and sharper understanding of multifaceted nature of cancer. Next-generation sequencing technologies have leveraged our existing knowledge related to intra- and inter-tumor heterogeneity to the next level. Functional genomics have opened new horizons to explore deregulated signaling pathways in different cancers. Therapeutic targeting of deregulated oncogenic signaling cascades by products obtained from natural sources has shown promising results. Epigallocatechin-3-gallate (EGCG) has emerged as a distinguished chemopreventive product because of its ability to regulate a myriad of oncogenic signaling pathways. Based on its scientifically approved anticancer activity and encouraging results obtained from preclinical trials, it is also being tested in various phases of clinical trials. A series of clinical trials associated with green tea extracts and EGCG are providing clues about significant potential of EGCG to mechanistically modulate wide ranging signal transduction cascades. In this review, we comprehensively analyzed regulation of JAK/STAT, Wnt/β-catenin, TGF/SMAD, SHH/GLI, NOTCH pathways by EGCG. We also discussed most recent evidence related to the ability of EGCG to modulate non-coding RNAs in different cancers. Methylation of the genome is also a widely studied mechanism and EGCG has been shown to modulate DNA methyltransferases (DNMTs) and protein enhancer of zeste-2 (EZH2) in multiple cancers. Moreover, the use of nanoformulations to increase the bioavailability and thus efficacy of EGCG will be also addressed. Better understanding of the pleiotropic abilities of EGCG to modulate intracellular pathways along with the development of effective EGCG delivery vehicles will be helpful in getting a step closer to individualized medicines.
Highlights
Genomic approaches such as whole genome sequencing and genetic mapping have helped considerably in the identification of many genetic variants in multiple components of cell signaling pathways
Western blot assay clearly indicated that EGCG dose-dependently reduced protein levels of Notch1 in cancer stem cells (CSCs) of head and neck squamous carcinoma (HNSC)
CD44 was overexpressed in A549-cisplatin resistant lung cancer cells but EGCG treatment exerted repressive effects on CD44 levels by enhancing miR-485-mediated targeting of CD44 [61]
Summary
Genomic approaches such as whole genome sequencing and genetic mapping have helped considerably in the identification of many genetic variants in multiple components of cell signaling pathways. 2020, 12, 951with green tea extracts and EGCG mainly through inhibition of JAK2/STAT1 after signaling in A549 cells [15]. EGCG mediated inhibition of JAK/STAT signaling via activation of negative regulators (SHP-2) and administered EGCG mitigated cisplatin-induced hearing loss along with a marked reduction in the loss inactivation of positive regulators (JAK1, JAK2) has gradually gained appreciation. EGCG reduced mRNA levels of PD-L1 in F10-OVA cells and enhanced expression of interleukin-2 in tumor-specific CD3+ T cells [15] These findings suggested that green tea catechin acted as a useful immunological checkpoint inhibitor. Vandetanib and EGCG effectively reduced phosphorylated levels of EGFR2 and VEGFR2 in drug-resistant breast cancer cells [18]. Tamoxifen worked powerfully with EGCG and reduced the levels of EGFR1, VEGF, and VEGFR1 in breast cancer cells [19]. EGCG remarkably reduced phosphorylated levels of VEGFR1 and VEGFR2 in B-cell chronic lymphocytic leukemia cells [24]
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