Fig. 6.
Differential role of Ref-1/APE1 redox inhibition in sensory neurons vs. tumor cells. a In tumor cells, Ref-1/APE1 redox inhibition as multiple downstream effects on tumor growth, survival, migration and tumor inflammation.31, 106, 253, 254, 257 b In sensory neuron cells such as DRG neurons, the addition of APX3330 does not have a negative effect on the cells, and promotes survival and functional protection through enhancement of Ref-1/APE1 DNA repair activity against oxidative DNA damaging agents (e.g., cisplatin, oxaliplatin) that invoked the DNA BER pathway. In the lower right panel, APX3330 attenuates neurotoxicity induced by systemic administration of cisplatin to tumor-bearing mice. c Treatment paradigm for investigation of the effects of cisplatin and APX3330 on DNA damage within DRG. Neuroblastoma cells were implanted subcutaneously into the right flanks of 6-week-old male NSG mice and allowed to proliferate until tumor volumes ≥150 mm3. Mice were then randomized for treatment with cisplatin ± APX3330 treatment. Cisplatin and APX3330 were administered concurrently for 3 weeks (Day 0–Day 17) and endpoints of neuronal toxicity were assessed within the DRG of mice at several time points following the last dose of cisplatin. d Representative blots demonstrating pH2A.X immunoreactivity at D24 and D31. e Quantification of pH2A.X immunoreactivity. An asterisk indicates statistical significance between D18 and D24 (e) as determined by a one-way ANOVA with Tukey’s post test with p < 0.05. A cross indicates statistical significance between Veh/Veh group and the Veh/Cis group (e) as determined by a two-way ANOVA with Bonferroni’s posttest with p < 0.05