Jiang Jiuliang, Yang Pingping, Xu Xinyu, Yuan Huixiong, Zhu Haitao
School of Clinical Medicine, Guizhou Medical University.
Department of Laboratory Medicine, People's Hospital of Qiannan Prefecture, Guizhou.
Anticancer Drugs. 2024 Oct 1;35(9):789-805. doi: 10.1097/CAD.0000000000001631. Epub 2024 Jun 26.
Liver cancer is a prevalent malignant tumor globally. The newly approved first-line drug, donafenib, is a novel oral small molecule multi-tyrosine kinase inhibitor that has significant antitumor effects on liver cancer. This study aims to investigate the antitumor effects of donafenib on liver cancer and to explore its potential mechanisms. Donafenib significantly inhibited the viability of Huh-7 and HCCLM3 cells, inhibited malignant cell proliferation, and promoted cell apoptosis, as demonstrated by CCK-8, EdU, and Calcein/PI (propidium iodide) staining experiments. The results of DNA damage detection experiments and western blot analysis indicate that donafenib caused considerable DNA damage in liver cancer cells. The analysis of poly (ADP-ribose) polymerase 1 (PARP1) in liver cancer patients using online bioinformatics data websites such as TIMER2.0, GEPIA, UALCAN, cBioPortal, Kaplan-Meier Plotter, and HPA revealed a high expression of PARP1, which is associated with poor prognosis. Molecular docking and western blot analysis demonstrated that donafenib can directly target and downregulate the protein expression of PARP1, a DNA damage repair protein, thereby promoting DNA damage in liver cancer cells. Western blot and immunofluorescence detection showed that the group treated with donafenib combined with PARP1 inhibitor had significantly higher expression of γ-H2AX and 8-OHdG compared to the groups treated with donafenib or PARP1 inhibitors alone, the combined treatment suppresses the expression of the antiapoptotic protein Bcl2 and enhances the protein expression level of the proapoptotic protein Bcl-2-associated X protein (BAX). These data suggest that the combination of donafenib and a PARP1 inhibitor results in more significant DNA damage in cells and promotes cell apoptosis. Thus, the combination of donafenib and PARP1 inhibitors has the potential to be a treatment option for liver cancer.
肝癌是全球一种常见的恶性肿瘤。新获批的一线药物多纳非尼是一种新型口服小分子多酪氨酸激酶抑制剂，对肝癌具有显著的抗肿瘤作用。本研究旨在探讨多纳非尼对肝癌的抗肿瘤作用，并探索其潜在机制。CCK-8、EdU和钙黄绿素/碘化丙啶（PI）染色实验表明，多纳非尼显著抑制Huh-7和HCCLM3细胞的活力，抑制恶性细胞增殖，并促进细胞凋亡。DNA损伤检测实验和蛋白质印迹分析结果表明，多纳非尼在肝癌细胞中引起了相当程度的DNA损伤。使用TIMER2.0、GEPIA、UALCAN、cBioPortal、Kaplan-Meier Plotter和HPA等在线生物信息学数据网站对肝癌患者的聚（ADP-核糖）聚合酶1（PARP1）进行分析，结果显示PARP1高表达，且与预后不良相关。分子对接和蛋白质印迹分析表明，多纳非尼可直接靶向并下调DNA损伤修复蛋白PARP1的蛋白表达，从而促进肝癌细胞中的DNA损伤。蛋白质印迹和免疫荧光检测显示，与单独使用多纳非尼或PARP1抑制剂处理的组相比，多纳非尼联合PARP1抑制剂处理的组γ-H2AX和8-羟基脱氧鸟苷（8-OHdG）的表达显著更高，联合治疗抑制了抗凋亡蛋白Bcl-2的表达，并提高了促凋亡蛋白Bcl-2相关X蛋白（BAX）的蛋白表达水平。这些数据表明，多纳非尼与PARP1抑制剂联合使用可在细胞中导致更显著的DNA损伤并促进细胞凋亡。因此，多纳非尼与PARP1抑制剂联合使用有可能成为肝癌的一种治疗选择。
