Fig. 5: The response of NSCLC to ALDH1 and ALDH3 inhibition is synergistically enhanced by ROS-inducing agents or inhibitors of the GSH cellular antioxidant system. | Oncogene

Fig. 5: The response of NSCLC to ALDH1 and ALDH3 inhibition is synergistically enhanced by ROS-inducing agents or inhibitors of the GSH cellular antioxidant system.

From: Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer

Fig. 5

a Three-dimensional plot showing the distribution of IC50 values for DIMATE and the total intracellular GSH and ROS levels in each of the 26 NSCLC cell lines. The square highlights cells showing high sensitivity to DIMATE, which are also the cells with high ROS levels and low to moderate GSH levels. b ROC curves for the response of NSCLC cells to DIMATE vs. ROS levels, total intracellular GSH levels and the ROS:GSH ratio. (AUC = 0.67, 0.56, 0.93, respectively). ROC receiver operating characteristic; AUC area under the ROC curve. c Relative viability of H460 cells treated with 15 µM DIMATE, 100 µM BSO or 50 µM BCNU alone and in the indicated combinations as a function of time. The drug vehicle was used as the control. A significant decrease in viability was observed in H460 cells treated with DIMATE plus BSO or DIMATE plus BCNU compared to cells treated with the control or compound alone (P < 0.001; t-test). The data are expressed as the mean fold changes in cell number relative to day 1 ± SDs (N = 3). d Dose-response curve for the viability of HCC827 cells exposed for 48 hours to DIMATE in the presence or absence of PCN. The IC50 values for the different conditions are provided in the graph. The inner panel shows that 40 μM PCN exhibited no cytotoxicity at the indicated incubation times. The error bars indicate the SD (N = 4). e Schematic representation of the strategy used to evaluate the viability of H460 and HCC827 cells when transient depletion of ALDH1 and/or ALDH3 was combined with the reduction in redox capacity induced by GCLC shRNA or CAT shRNA, respectively. f, g Viability of stable H460 cells expressing dox-inducible GCLC shRNA and HCC827 cells expressing dox-inducible CAT shRNA as described in e with ALDH1 or ALDH3 depletion as indicated in the x axis at the 96-h time point. The data are expressed as percentages relative to control cells. The error bars indicate the SDs. (N = 3); **P < 0.005.

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