Genistein suppresses the proliferation of telomerase‐negative cells

Abstract

In both tumor and yeast cells that lack telomerase, telomeres are maintained via an alternative recombination mechanism. In this study, we tested genistein, a potential TOP2 inhibitor required for telomere–telomere recombination, on the repression of telomere–telomere recombination. Genistein on the repression of type II recombination on a tlc1 yeast strain was examined by the telomeric DNA structures using Southern blot analysis. Telomere patterns of freshly dissected tlc1 spores containing an empty plasmid (pYES2) or a yeast TOP2 (yTOP2) plasmid were analyzed. The results indicated that the reintroduction of TOP2 recovered the type II pattern, implying genistein in the blockage of type II survivors in the tlc1 strain. The effects of genistein on both tlc1 and tlc1 rad 51 strains in liquid and solid mediums were also examined. Finally, treatment of 10 μmol/L of genistein showed inhibitory effect on the growth of telomerase‐negative U2OS alternative lengthening of telomere (ALT) cells, but not in telomerase‐positive HCT116 cells. These results provide evidences that the inhibitory effects of genistein on telomerase‐negative cells depend on type II recombination pathway in yeast and the ALT pathway in human tumors.

Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner

“…It has been reported that genistein affects proliferations of oviductal epithelial cells [33], melanoma cells [34], telomerase-negative cells [35], and other cancer cells [36]. In consistent, current studies showed that genistein inhibited the proliferation of CHOK1, CHO3.1, CHO3.3 and HCT116 cells in a concentration-and time-dependent manner (Fig.…”

ALT Positivity in Human Cancers: Prevalence and Clinical Insights

“…The third strategy employs DNA topoisomerase 2 (TOP2) inhibitors. A recent study using yeast and U2OS cells suggests that selective TOP2 inhibition, with genistein, may kill ALT+ cells and not the ALT− ones [ 198 ]. TOP2 is thought to be required for telomere-telomere recombination and chromatin maintenance, phenomena both integral to the ALT mechanism [ 199 , 200 ].…”

Combining old and new concepts in targeting telomerase for cancer therapy: transient, immediate, complete and combinatory attack (TICCA)

“…DNA topoisomerase 2 (TOP2) inhibitors : TOP2 is required for telomere-telomere recombination and chromatin maintenance, two ALT characteristics [ 227 , 228 ], suggesting possible specificity for ALT. Indeed, TOP2 inhibition with genistein may kill ALT + cells and not the ALT − cells [ 229 ]. However, this finding was not confirmed with other inhibitors displaying better anti-proliferative effects in TEL + HeLa cells.…”

“…An armada of methodologies is available including oligonucleotide inhibitors, small molecule hTERT inhibitors, G4-stabilizing compounds with improved selectivity [ 223 – 226 ], immunotherapeutic approaches [ 118 – 122 ], telomerase-directed gene therapy using telomerase promoters of cancer cells as targets [ 130 ], conventional and Crisp/Cas9 induced alternative splicing [ 88 , 89 , 132 ], alternative splicing with splice-switching oligonucleotides [ 133 , 134 – 137 , 206 , 208 ], the use of phytochemicals with a wide variety of different targets [ 257 ]; Crisp/Cas9 based and other telomere deprotection measures [ 183 , 184 , 187 ]; the use of ATR inhibitors [ 217 , 218 – 221 ]. DNA topoisomerase 2 (TOP2) inhibitors [ 229 , 230 ] and poly ADP ribose polymerase (PARP) inhibitors (that may work in ALT + cells) [ 99 ] and targeted oncolytic virotherapy with ALT specific targets such as HSV-1 lacking ICP0 [ 232 ].…”