Fig. 3

Radiation skin injury is mitigated by the senolytic agent, 17-DMAG. Seven days after 30 Gy radiation (day 0), treatment with 17-DMAG was initiated. Panel A: Typical skin damage in a mouse six weeks after 30 Gy radiation alone. Panel B: Typical skin damage to a mouse at the same time point after 30 Gy plus 17-DMAG. Panel C: The time course of skin damage following 30 Gy alone or 30 Gy plus 17-DMAG using a semi-quantitative scale, and, Panel D, the corresponding leg contraction. Curves were statistically different; as an example, standard deviations illustrated at day 50 show a statistically significant separation between groups. Skin injury semi-quantitative scale is 1 = normal, 2 = erythema, 3 = dry desquamation, 4 = moist desquamation and 5 = necrosis. Typically, scores of 3 and under resolve with time whereas scores greater than 3 do not. Each curve is from 5 mice. Error bars shown represent standard deviation. Panels E and F show the effect of a senolytic agent and senostatic agent to increase the therapeutic gain; each strategy elicits an anti-cancer effect and the combined administration mitigates normal tissue radiation injury. Panel E illustrates an increased A-549 tumor growth delay following administration of either a senolytic agent, 17-DMAG or a senostatic agent, metformin. At day 35, tumor volumes following 15 Gy + metformin was statistically different from that of 15 Gy alone (other groups did not reach significance and only trends were observed). Panel F shows that combining a senolytic and senostatic agent mitigates radiation-induced skin injury in C57BL/6 mice (data from a separate experiment as that shown in A–D). Note that combining the senostatic (metformin) with a senolytic (17-DMAG) did not abrogate the mitigation of radiation injury. At day 50, average damage score of mice receiving either 30 Gy + 17-DMAG or 30 Gy + 17-DMAG + metformin were statistically different from that of mice receiving 30 Gy radiation alone (although adding metformin did not improve average damage score). Each data point represents at least 10 mice for tumor growth delay and at least 5 mice for skin damage study. Error bars shown represent the standard deviation