The Effect of Green and Black Tea Polyphenols on BRCA2 Deficient Chinese Hamster Cells by Synthetic Lethality through PARP Inhibition

Abstract

Tea polyphenols are known antioxidants presenting health benefits due to their observed cellular activities. In this study, two tea polyphenols, epigallocatechin gallate, which is common in green tea, and theaflavin, which is common in black tea, were investigated for their PARP inhibitory activity and selective cytotoxicity to BRCA2 mutated cells. The observed cytotoxicity of these polyphenols to BRCA2 deficient cells is believed to be a result of PARP inhibition induced synthetic lethality. Chinese hamster V79 cells and their BRCA2 deficient mutant V-C8, and V-C8 with gene complemented cells were tested against epigallocatechin gallate and theaflavin. In addition, Chinese hamster ovary (CHO) wild-type cells and rad51D mutant 51D1 cells were used to further investigate the synthetic lethality of these molecules. The suspected PARP inhibitory activity of epigallocatechin and theaflavin was confirmed through in vitro and in vivo experiments. Epigallocatechin gallate showed a two-fold increase of cytotoxicity to V-C8 cells compared to V79 and gene complimented cells. Compared to CHO wild type cells, 51D1 cells also showed elevated cytotoxicity following treatment with epigallocatechin gallate. Theaflavin, however, showed a similar increase of cytotoxicity to VC8 compared to V79 and gene corrected cells, but did not show elevation of cytotoxicity towards rad51D mutant cells compared to CHO cells. Elevation of sister chromatid exchange formation was observed in both tea polyphenol treatments. Polyphenol treatment induced more micronuclei formation in BRCA2 deficient cells and rad51D deficient cells when compared against the respective wild type cells. In conclusion, tea polyphenols, epigallocatechin gallate, and theaflavin may present selective cytotoxicity to BRCA2 deficient cells through synthetic lethality induced by PARP inhibition.

Restoring chemo-sensitivity to temozolomide via targeted inhibition of poly (ADP-ribose) polymerase-1 by naringin in glioblastoma

“…The presence of polyphenolic structure in naringin is the principal reason for complementary and multiple binding to the target, which is also in collateral with plenty of literature. (Alqahtani et al 2019;Su et al 2017).…”

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

“…Tea polyphenols affect regulatory systems of cells and may produce an inhibitory effect on various stages of carcinogenesis: inflammatory processes, cell transformation, proliferation, apoptosis, metastasis, and invasion [ 107 , 137 , 138 , 139 , 140 ]. It was found that EGCG and TF cause synthetic lethality in BRCA2-deficient cells through a PARP-dependent mechanism [ 141 ]. EGCG inhibits PARP-1 more effectively than TF, which is probably due to the presence of a haloyl group.…”

Epigallocatechin Gallate Affects the Structure of Chromatosomes, Nucleosomes and Their Complexes with PARP1

“…Since EGCG is an inhibitor of PARP1 [ 16 ], we studied the effect of EGCG on the interaction of PARP1 with nucleosomes.…”

“…The modulation of gene expression with EGCG is not accompanied by genotoxicity [ 10 ], and is assumed to be associated with the inhibition of different transcription factors, DNA methyltransferase and class I histone deacetylases [ 9 , 11 , 12 ]. Nucleus-associated mechanisms of EGCG action include the poisoning of topoisomerases I and II and the inhibition of poly(ADPribose)polymerase 1 (PARP1) [ 9 , 13 , 14 , 15 , 16 ]. PARP1 is a sensor of DNA damage, and recruits DNA repair proteins to DNA lesions [ 17 ].…”