Fig. 7

DMEA identifies potential senescence-inducing and senolytic drug MOAs for primary HMECs. A Schematic detailing how the proteomic signature of replicative senescence in primary HMECs [46] was used to identify either senescence-inducing or senolytic drug MOAs. B DMEA results for senescence-inducing drug MOAs. (Left) Volcano plot of NES versus − log₁₀(p value) for drug MOAs from DMEA. Red text indicates MOAs with p value < 0.05 and FDR < 0.25. (Right) Mountain plot showing the positive enrichment of the proteasome inhibitor MOA in the rank-ordered drug list of CMap L1000 connectivity scores. The proteasome inhibitors with the most positive connectivity scores are highlighted. C DMEA results for senolytic drug MOAs. (Left) Volcano plot of NES versus − log₁₀(p value) for drug MOAs from DMEA. Red text indicates MOAs with p value < 0.05 and FDR < 0.25. (Right) Mountain plot showing the positive enrichment of the EGFR inhibitor MOA in the rank-ordered drug list of correlation coefficients. The EGFR inhibitors with the most positive correlation coefficients are highlighted. D The EGFR inhibitors dacomitinib and AZD8931 and the senolytic compound navitoclax exhibited senolytic activity in HMECs. Proliferating HMECs (PD ~ 12) were treated with DMSO or 2 μM triapine for 3 days to induce proliferating or senescent phenotypes, respectively, as in our previous work [53]. Proliferating and senescent HMECs were then treated with DMSO (negative control), 100 nM/500 nM dacomitinib, 100 nM / 500 nM AZD8931, or 100 / 500 nM navitoclax for 3 days, after which cell viability and live cell number were measured by trypan blue staining. The live cell number was normalized to the number of live cells present at the time of drug treatment. * and ** represent p < 0.05 and 0.01, respectively, compared to the senescent DMSO control calculated by Student’s t-test