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

Abstract

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-, druginduced 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.

Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging

“…Senescence of senescent cells or telomere attrition is an important cause of senescence, and therefore, anti-aging strategies by scavenging senescent cells and reducing the attrition of telomeres are also potential pharmacological strategies. 30,31 Current research suggests that aging is primarily associated with nutrient sensing disorders, mitochondrial dysfunction, and cellular senescence, 23 but there are many questions about how to reverse or delay aging, which needs to be further explored.…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Since TIS involves the increased expression of BCL-2, targeting BCL-2 may exert anticancer effects. BCL2-targeting drugs, including ABT-737 and ABT-263 (navitoclax), natural substances, such as artesunate, fisetin, and curcumin, showed senolytic effects in glioblastoma cells and non-transformed cells [ 83 , 167 ]. ABT-263 eliminated senescent cells and enhanced the efficacy of olaparib, a PARP inhibitor, in both breast and ovarian cancer cell lines [ 168 ].…”

“…Cancer cells emerging from senescence display higher anticancer drug resistance than cancer cells without senescence [ 46 ]. Senescent cells display resistance to apoptosis owing to high level of BCL-2 [ 83 ], suggesting the role of senescence in therapeutic resistance. Lapatinib and fulvestrant (EGFR and HER2 inhibitors) treatment induced apoptosis in chemotherapy-induced senescent breast cancer cells [ 84 ].…”

“…Lapatinib and fulvestrant (EGFR and HER2 inhibitors) treatment induced apoptosis in chemotherapy-induced senescent breast cancer cells [ 84 ]. Senescence induced by radiation, oncogenes, and chemicals increased the expression of BCL-2 in non-transformed retinal pigment endothelial cells and fibroblasts [ 83 ]. Thus, targeting BCL-2 or other anti-apoptotic proteins can eliminate senescent cancer cells (senolysis or senolytic therapy).…”

STAT3 inhibitor Stattic and its analogues inhibit STAT3 phosphorylation and modulate cytokine secretion in senescent tumour cells

“…our previous studies demonstrated that tumour growth of proliferating murine Tc-1 HPV-16-associated cancer cells in syngeneic mice was accelerated by co-administration of Tc-1 or TraMP-c2 cancer cells that were made senescent by pre-treatment with the anti-cancer agent docetaxel (dTX) (22). dTX was also successfully used for the induction of senescence in human cell lines (23). These studies suggested that dTX-treated cells can be a useful model for studies focused on senescent cells.…”