EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin–angiotensin system

Mingchuan Yang; Ximing Wu; Yufeng He; Xiuli Li; Lumin Yang; Tingting Song; Fuming Wang; Chung S. Yang; Jinsong Zhang

doi:10.1039/D3FO03795A

EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin–angiotensin system

Mingchuan Yang,†^a Ximing Wu,†^b Yufeng He,^a Xiuli Li,^a Lumin Yang,^a Tingting Song,^a Fuming Wang,^a Chung S. Yang

*^cd and Jinsong Zhang

*^ad

Author affiliations

* Corresponding authors

^a State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Anhui Agricultural University, Hefei, Anhui, China
E-mail: zjs@ahau.edu.cn

^b Anhui Engineering Laboratory for Medicinal and Food Homologous Natural Resources Exploration, School of Biological and Food Engineering, Hefei Normal University, Hefei, Anhui, China

^c Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, USA
E-mail: csyang@pharmacy.rutgers.edu

^d Joint International Research Laboratory of Tea Chemistry and Health Effects, State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China

Abstract

Green tea polyphenol (−)-Epigallocatechin-3-gallate (EGCG) has been well studied for its biological activities in the prevention of chronic diseases. However, the biological activities of EGCG oxidation-derived polymers remain unclear. Previously, we found that these polymers accumulated in intraperitoneal tissues after intraperitoneal injection and gained an advantage over native EGCG in increasing insulin sensitivity via regulating the renin–angiotensin system (RAS) in type 2 diabetic mice. The present study determined the pro-apoptosis activities and anticancer mechanisms of the EGCG oxidation-derived polymer preparation (the >10 kDa EGCG polymers) in digestive tract cancer cells. Upon incubation of the >10 kDa EGCG polymers with CaCo2 colon cancer cells, these polymers coated the cell surface and regulated multiple components of the RAS in favor of cancer inhibition, including the downregulation of angiotensin-converting enzyme (ACE), angiotensin-II (AngII) and AngII receptor type 1 (AT1R) in the pro-tumor axis, as well as the upregulation of angiotensin-converting enzyme 2 (ACE2) and angiotensin1–7 (Ang(1–7)) in the anti-tumor axis. The treatment also markedly increased angiotensinogen (AGT), which is the precursor of the angiotensin peptides. The regulation of these RAS components occurred prior to apoptosis. Similar pro-apoptotic mechanisms of the >10 kDa EGCG polymers, were also observed in TCA8113 oral cancer cells. The >10 kDa EGCG polymers exhibited compromised activities in scavenging or initiating reactive oxygen species compared to EGCG, but gained a higher reactivity toward sulfhydryl groups, including protein cysteine thiols. We propose that the polymers bind onto the cell surface and regulate multiple RAS components by reacting with the sulfhydryl groups on the ectodomains of transmembrane proteins.

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EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin–angiotensin system

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EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin–angiotensin system

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