Varga Dóra, Szentirmai Anna, Szarka András
Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary.
Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary.
Molecules. 2025 Feb 24;30(5):1031. doi: 10.3390/molecules30051031.
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, HO). 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.
我们的研究团队旨在优化药理抗坏血酸（Ph-Asc）诱导的癌细胞死亡。为了减少开发所需的时间和资源，我们在先前的研究中采用了计算机系统生物学方法、一种已获批准的药物以及一种温和的生物活性化合物。结果表明，Ph-Asc和白藜芦醇（RES）均会导致DNA双链断裂（DSBs），而氯喹（CQ）处理以自噬非依赖的方式增强了Ph-Asc和RES的细胞毒性作用。在本研究中，我们旨在通过比较Ph-Asc、CQ和RES与目前研究的三种化合物（甲萘醌、RSL3、HO）的DNA损伤能力、对细胞生物能量状态的影响、活性氧（ROS）和脂质ROS生成能力，进一步阐明它们的细胞毒性机制。可以评估，DSBs的诱导肯定是它们作用机制的一个共同点；此外，观察到的因所研究的处理导致的癌细胞死亡与生物能量状态无关。与其他研究的化合物相反，CQ的DNA损伤作用似乎与ROS无关。令人惊讶的是，著名的铁死亡诱导剂RSL3在胰腺导管腺癌（PDAC）Mia PaCa-2细胞系中无法诱导脂质过氧化。同时，它诱导了DNA中的DSBs，并且RSL3诱导的细胞死亡不能被著名的铁死亡抑制剂所阻断。所有这些观察结果表明该细胞系具有铁死亡抗性。观察到的RSL3的DNA损伤作用无疑为抗癌研究开辟了新的视角。
