Research for a Common Thread: Insights into the Mechanisms of Six Potential Anticancer Agents

Our research group aimed for the optimization of pharmacologic ascorbate (Ph-Asc)-induced cancer cell death. To reduce the required time and resources needed for development, an in silico system biological approach, an already approved medication, and a mild bioactive compound were used in our previous studies. It was revealed that both Ph-Asc and resveratrol (RES) caused DSBs in the DNA, and chloroquine (CQ) treatment amplified the cytotoxic effect of both Ph-Asc and RES in an autophagy independent way. In the present study, we aimed at the further clarification of the cytotoxic mechanism of Ph-Asc, CQ, and RES by comparing their DNA damaging abilities, effects on the cells' bioenergetic status, ROS, and lipid ROS generation abilities with those of the three currently investigated compounds (menadione, RSL3, H₂O₂). It could be assessed that the induction of DSBs is certainly a common point of their mechanism of action; furthermore, the observed cancer cell death due to the investigated treatments are independent of the bioenergetic status. Contrary to other investigated compounds, the DNA damaging effect of CQ seemed to be ROS independent. Surprisingly, the well-known ferroptosis inducer RSL3 was unable to induce lipid peroxidation in the pancreas ductal adenocarcinoma (PDAC) Mia PaCa-2 cell line. At the same time, it induced DSBs in the DNA, and the RSL3-induced cell death could not be suspended by the well-known ferroptosis inhibitors. All these observations suggest the ferroptosis resistance of this cell line. The observed DNA damaging effect of RSL3 definitely creates a new perspective in anticancer research.