Makk-Merczel Kinga, Varga Dóra, Hajdinák Péter, Szarka András
Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Budapest, Hungary.
Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary.
Biofactors. 2024 Sep-Oct;50(5):980-996. doi: 10.1002/biof.2050. Epub 2024 Mar 15.
Currently, a diagnosis with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) means a death warrant, so finding efficient therapeutic options is a pressing issue. Here, we presented that pharmacologic ascorbate, chloroquine and resveratrol co-treatment exerted a synergistic cytotoxic effect on PDAC cell lines. The observed synergistic cytotoxicity was a general feature in all investigated cancer cell lines independent of the KRAS mutational status and seems to be independent of the autophagy inhibitory effect of chloroquine. Furthermore, it seems that apoptosis and necroptosis are also not likely to play any role in the cytotoxicity of chloroquine. Both pharmacologic ascorbate and resveratrol caused double-strand DNA breaks accompanied by cell cycle arrest. It seems resveratrol-induced cytotoxicity is independent of reactive oxygen species (ROS) generation and accompanied by a significant elevation of caspase-3/7 activity, while pharmacologic ascorbate-induced cytotoxicity shows strong ROS dependence but proved to be caspase-independent. Our results are particularly important since ascorbate and resveratrol are natural compounds without significant harmful effects on normal cells, and chloroquine is a known antimalarial drug that can easily be repurposed.
目前，诊断为KRAS突变型胰腺导管腺癌（PDAC）意味着宣判死刑，因此寻找有效的治疗方案是一个紧迫的问题。在此，我们提出药理学维生素C、氯喹和白藜芦醇联合治疗对PDAC细胞系具有协同细胞毒性作用。观察到的协同细胞毒性是所有研究的癌细胞系的一个普遍特征，与KRAS突变状态无关，似乎也与氯喹的自噬抑制作用无关。此外，凋亡和坏死性凋亡似乎也不太可能在氯喹的细胞毒性中起任何作用。药理学维生素C和白藜芦醇均导致双链DNA断裂并伴有细胞周期停滞。白藜芦醇诱导的细胞毒性似乎与活性氧（ROS）生成无关，并伴有caspase-3/7活性的显著升高，而药理学维生素C诱导的细胞毒性表现出强烈的ROS依赖性，但被证明与caspase无关。我们的结果尤为重要，因为维生素C和白藜芦醇是天然化合物，对正常细胞没有明显有害影响，而氯喹是一种已知的抗疟药物，很容易被重新利用。
