Effects and Related Mechanisms of the Senolytic Agent ABT-263 on the Survival of Irradiated A549 and Ca9-22 Cancer Cells.

Kota Sato,Hironori Yoshino,Soichiro Iwasaki

doi:10.3390/ijms222413233

Kota Sato, Hironori Yoshino + Show 1 more

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https://doi.org/10.3390/ijms222413233

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Abstract

Senolytic agents eliminate senescent cells and are expected to reduce senescent cell-mediated adverse effects in cancer therapy. However, the effects of senolytic agents on the survival of irradiated cancer cells remain unknown. Here, the effects of the senolytic agent ABT-263 on the survival of irradiated A549 and Ca9-22 cancer cells were investigated. ABT-263 was added to the culture medium after irradiation. SA-β-gal activity and cell size, which are hallmarks of cell senescence, were evaluated using a flow cytometer. The colony-forming assay and annexin V staining were performed to test cell survival. We first confirmed that radiation increased the proportion of cells with high SA-β-gal activity and that ABT-263 decreased it. Of note, ABT-263 decreased the survival of irradiated cancer cells and increased the proportion of radiation-induced annexin V+ cells. Furthermore, the caspase inhibitor suppressed the ABT-263-induced decrease in the survival of irradiated cells. Intriguingly, ABT-263 decreased the proportion of SA-β-gal low-activity/large cells in the irradiated A549 cells, which was recovered by the caspase inhibitor. Together, these findings suggest that populations maintaining the ability to proliferate existed among the irradiated cancer cells showing senescence-related features and that ABT-263 eliminated the population, which led to decreased survival of irradiated cancer cells.

Highlights

In normal mammalian somatic cells, the telomere DNA at the end of each chromosome shortens with each cell division and after a certain number of divisions, cell proliferation irreversibly stops [1]
The results showed that ABT-263 decreased the survival of irradiated cancer cells
When ABT-263 (5 or 10 μM) was added to the culture at 24 h after 6 Gy-irradiation, When ABT-263 (5 or 10 μM) was added to the culture at 24 h after 6 Gy-irradiation, the proportions of A549 and Ca9-22 cells with high SA-β-gal activity were significantly the proportions of A549 and Ca9-22 cells with high SA-β-gal activity were significantly decreased (Figure 1C). These results suggest that ABT-263 suppressed the proliferation of decreased (Figure 1C). These results suggest that ABT-263 suppressed the proliferation of radiation-induced senescence-like cells

Summary

Introduction

In normal mammalian somatic cells, the telomere DNA at the end of each chromosome shortens with each cell division and after a certain number of divisions, cell proliferation irreversibly stops (replicative senescence) [1]. Recent evidence has shown that senescent cells secrete various bioactive substances such as inflammatory cytokines and proteases [5], which is known as the senescence-associated secretory phenotype (SASP). These secreted substances induce inflammation of the surrounding cells and tissues [6]

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