Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells

by Selleckchem | Aug 30 2023

Accumulation of senescent cells in tissues with advancing age participates in the pathogenesis of several human age-associated diseases. Specific senescent secretome, the resistance of senescent cells to apoptotic stimuli, and lack of immune system response contribute to the accumulation of senescent cells and their adverse effects in tissues. Inhibition of antiapoptotic machinery, augmented in senescent cells, by BCL-2 protein family inhibitors represents a promising approach to eliminate senescent cells from tissues. 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.

Comments:

The study you mentioned explores the potential of using BCL-2 protein family inhibitors, specifically BH3 mimetics, to eliminate senescent cells from tissues. Senescent cells are cells that have entered a state of irreversible growth arrest and are associated with age-related diseases. The accumulation of senescent cells in tissues is believed to contribute to the development of these diseases.

The researchers conducted experiments using human non-transformed cells (RPE-1, BJ, and MRC-5) and induced senescence through various methods such as ionizing radiation, oncogenes, drugs, and replicative senescence. They found that combining MCL-1 selective inhibitors with other BH3 mimetics showed a synergistic effect in eliminating senescent cells.

To understand the mechanism behind this synergy, the researchers investigated the surviving subpopulation of cells that were resistant to individually applied BCL-2 family inhibitors (ABT-737/ABT-263, MIK665, ABT-199, and S63845). They discovered that these cells had elevated levels of MCL-1 compared to untreated control cells. This finding suggests the presence of a subset of senescent cells within the original population that expresses high levels of MCL-1 and is resistant to BCL-2 inhibitors.

Overall, the study demonstrates that combining BCL-2 inhibitors can be beneficial in eliminating senescent cells, potentially allowing the use of lower and less toxic doses of drugs compared to monotherapy. By targeting multiple members of the BCL-2 protein family, the researchers aim to overcome the resistance of certain senescent cell subsets to individual inhibitors.

It's worth noting that the information provided is a summary of the study you mentioned. If you have any specific questions or would like further clarification on certain aspects, please let me know.