Figure 5.

Reactive oxygen species (ROS)-based drug efficacy evaluation network. (A) Associations between index values and drug sensitivities across 1,066 cancer cell lines, using Spearman's rank correlation. Indexes I and II were important nodes for the network. Increasing index I mainly positively correlated with the IC50 of drugs targeting kinases on oncogenic pathways, while index II predominantly sensitized tumor cells to drugs targeting the PI3K/mTOR pathway, kinases, chromosome modifications, and the cell cycle. Red line = positive correlation, green line = negative correlation. Only drugs with moderate correlations are shown: yellow circle = drugs, blue circle = drug targets. (B) Heat map showing drugs with significant correlations with indexes I and II. The left panel shows index I and correlated drugs. The right panel shows index II and correlated drugs. With ROS accumulation increasing, the IC50 of four drugs correlated with index I increased; with oxidative stress degree deepening, normal cell cycle or DNA modification process would be affected and decrease the IC50 of the drugs correlated with index II. From green to pink, the IC50 increases; ****p < 0.0001. (C) By supplementing cells with exogenous H₂O₂, NF-κB and ERK were activated in these three cell lines; the STAT3 pathway was inhibited in glioma U87 and LN229 cell lines while activated in the THP-1 cell, whereas the AKT pathway was activated in U87 and THP-1 cell lines but inhibited in LN229 cell line. (D,E) The maximum concentration tolerance in the body of drugs from (B) and potential synergic strategies to decrease drug IC50. For drugs correlated with index I, N-acetyl-L-cysteine should be combined to increase drug efficacy, while for drugs correlated with index II, anti-oxidant inhibitor should be combined to increase drug efficacy.