RNA sequencing analysis of ARV825 target genes in senescent cells

Although cellular senescence acts primarily as a tumor suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumor-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify ARV825 as a promising senolytic drug. ARV825 treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by ARV825 increases the efficacy of chemotherapy against xenograft tumors in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control. Overall design: We performed an RNA sequencing (RNA-seq) analysis to identify the genes whose expression is downregulated by the ARV825 treatment in senescent human diploid fibroblasts )HDFs. Doxorubicin-induced senescent HDFs were treated with or without ARV825 (10 nM) for 4 days and were subjected to the RNAseq analysis.