Emerging evidence has shown that the
therapy-induced senescent growth arrest in
cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named
senolytics selectively target senescent cells and commit them into apoptosis. Accordingly,
senolytics have been proposed as adjuvant
cancer treatment to cull senescent
tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents,
sorafenib,
rapamycin, and
venetoclax for their senolytic potential in
doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents,
sorafenib (5 µM),
rapamycin (100 nM), or
venetoclax (10 µM), in the absence or presence of
doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-β-
galactosidase staining (SA-β-gal), while apoptosis was assessed using
annexin V-FITC/PI, and
Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human
Cancer Pathway Finder PCR array. The three agents reduced
doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of
doxorubicin compared with those treated only with
doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of
doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of
senolytics to reduce senescence-mediated resistance in
tumor cells and to enhance
chemotherapy efficacy.