Synergistic effects of BCL-2 family inhibitors contribute to selective clearance of senescent cells

Cellular senescence, a complex cellular response to stress characterized by the arrest of cell cycle progression, is a contributing factor to aging, according to a new research paper published in Aging

Specific senescent secretomes, resistance of senescent cells to apoptotic stimuli, and lack of immune system response are all responsible for the accumulation of senescent cells in tissues and their adverse effects

"In this study, with the goal of reducing toxicity and potential initial resistance to anti-aging BCL-2 inhibitor monotherapy, we explored a broad spectrum of anti-apoptotic factors encompassing BCL-2 and MCL-1 in human cells.

Researchers David Rysanek, Pavla Vasicova, Jayaprakash Narayana Kolla, David Sedlak, Ladislav Andera, Jiri Bartek and Zdenek Hodny from the Czech Academy of Sciences and the Danish Cancer Society Research Center aim to explore the synergy and selection of anti-apoptotic BCL-2 family-targeted compounds Sexual aging effects, especially BH3 mimetics

"Using ionizing radiation, oncogenes, drug-induced, and replicative senescence from human non-transformed cells RPE-1, BJ, and MRC-5, we discovered synergy of selective inhibitors of MCL-1 in combination with other BH3 mimics effect

To uncover the mechanism of this synergy, the team found that compared with untreated control cells, cells that were resistant to the single application of ABT-737/ABT-263, MIK665, ABT-199 and S63845 BCL-2 family inhibitors Subpopulations of surviving cells showed higher levels of MCL-1, suggesting the presence of subpopulations of cells expressing high levels of MCL-1 and, therefore, resistant to BCL-2 inhibitors in the primitive senescent cell population

Overall, the researchers found that the combination of BCL-2 inhibitors favored depletion of senescent cells and, as a result, allowed lower and potentially less toxic drug doses to overcome senescent cell subsets than monotherapy.

"In conclusion, we propose that the selective senolytic effects of non-MCL-1 BCL-2 family inhibitors, such as the known senolytics ABT-263, can be enhanced by co-treatment with selective MCL-1 inhibitors

article title

Synergistic action of BCL-2 family inhibitors facilitates selective clearance of senescent cells