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Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
Aging (Albany NY). 2022 Aug 8;14(undefined). doi: 10.18632/aging.204207.
David Rysanek 1, Pavla Vasicova 1, Jayaprakash Narayana Kolla 2, David Sedlak 2, Ladislav Andera 1 3, Jiri Bartek 1 4, Zdenek Hodny 1
Abstract:
...This study aimed to explore synergistic and selective senolytic effects of anti-apoptotic BCL-2 family targeting compounds, particularly BH3 mimetics. Using human non-transformed cells RPE-1, BJ, and MRC-5 brought to ionizing radiation-, oncogene-, drug-induced and replicative senescence, we found synergy in combining MCL-1 selective inhibitors with other BH3 mimetics. In an attempt to uncover the mechanism of such synergy, we revealed that the surviving subpopulation of cells resistant to individually applied ABT-737/ABT-263, MIK665, ABT-199, and S63845 BCL-2 family inhibitors showed elevated MCL-1 compared to untreated control cells indicating the presence of a subset of cells expressing high MCL-1 levels and, therefore, resistant to BCL-2 inhibitors within the original population of senescent cells. Overall, we found that combining BCL-2 inhibitors can be beneficial for eliminating senescent cells, thereby enabling use of lower, potentially less toxic, doses of drugs compared to monotherapy, thereby overcoming the resistance of the subpopulation of senescent cells to monotherapy.
PMID: 35951353
Free Full-Text: https://www.aging-us.com/article/204207/text
Tags: ABT-199, ABT-263, ABT-737, Bcl-2, cell culture, Mcl-1, MIK65, S63845, senolytics