Sorafenib, rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells

Homood M As Sobeai; Munirah Alohaydib; Ali R Alhoshani; Khalid Alhazzani; Mashal M Almutairi; Tareq Saleh; David A Gewirtz; Moureq R Alotiabi

doi:10.1016/j.jsps.2021.12.004

Sorafenib, rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells

Saudi Pharm J. 2022 Jan;30(1):91-101. doi: 10.1016/j.jsps.2021.12.004. Epub 2021 Dec 31.

Authors

Homood M As Sobeai¹, Munirah Alohaydib¹, Ali R Alhoshani¹, Khalid Alhazzani¹, Mashal M Almutairi¹, Tareq Saleh², David A Gewirtz^{3

4}, Moureq R Alotiabi¹

Affiliations

¹ Pharmacology and Toxicology Department, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
² Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan.
³ Departments of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
⁴ Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.

Abstract

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.

Keywords: Apoptosis; Doxorubicin; Rapamycin; Senescence; Senolytic; Sorafenib; Venetoclax.