Inhibition of MDM2 via Nutlin-3A: A Potential Therapeutic Approach for Pleural Mesotheliomas with MDM2-Induced Inactivation of Wild-Type P53

Figure 3

Induction of senescence in MPM cell lines by pemetrexed, cisplatin, and varying Nutlin-3A concentrations as well as varying Nutlin-3A concentrations combined with cisplatin. Figure 3 shows boxplots for cell viability/senescence for the three investigated MPM cell lines. On the y-axis RLU (relative luminescence units) are shown. High RLU indicate high cell viability, whereas low RLU indicate senescence. On the x-axis, the concentrations of the cytostatics applied and the control are shown. In all three MPM cell lines, 20μM Nutlin-3A showed the strongest inhibition of cell viability compared to the other single agent cytostatics and concentrations applied. This is true against other Nutlin-3A concentrations (NCI-H2052: p=0.021, MSTO-211H: p=0.007, NCI-H2452: p<0.001), cisplatin (NCI-H2052: p=0.021, MSTO-211H: p=0.018, NCI-H2452: p=0.004), pemetrexed (NCI-H2052: p=0.032, MSTO-211H: p=0.008, NCI-H2452: p=0.006), and a combination of both (NCI-H2052: p=0.003, MSTO-211H: p=0.002, NCI-H2452: p<0.001). Additionally, higher concentrations of Nutlin-3A (10μM, 20μM) combined with cisplatin regimen showed the strongest inhibition of cell viability compared to nowadays approved cytostatics, either as single agents (cisplatin: NCI-H2052: p=0.021, MSTO-211H: p=0.022, NCI-H2452: p=0.006; pemetrexed: NCI-H2052: p=0.014, MSTO-211H: p=0.029, NCI-H2452: p<0.001) or in combination (NCI-H2052: p=0.003, MSTO-211H: p=0.014, NCI-H2452: p<0.001).

(a)

(b)

(c)