Cui Zihan, Li Dapeng, Zhao Jun, Chen Kai
Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
Department of Oncology, The First Hospital Affiliated to Soochow University, Suzhou, 215000, China.
Free Radic Biol Med. 2022 Apr;183:106-124. doi: 10.1016/j.freeradbiomed.2022.03.003. Epub 2022 Mar 10.
Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide with limited effective therapies. Cisplatin (DDP), as the first-line treatment, is always served as a mainstay of chemotherapeutic agents in combination with other drugs for NSCLC treatment. Nevertheless, DDP-based therapy is limited due to the frequent development of chemoresistance and adverse effects. Herein, it is necessary to find a more effective therapeutic approach with less toxicity. Falnidamol (FLD) is a pyrimido-pyrimidine compound and exerts anti-cancer activity. In the present study, we found that FLD could strongly promote the cytotoxicity of DDP and markedly reduce the IC values to restrain the proliferation of NSCLC cells. Furthermore, combination of FLD and DDP remarkably induced G2/M cell cycle arrest, DNA damage and mitochondrial apoptosis, which was largely through the induction of reactive oxygen species (ROS). Additionally, FLD/DDP in combination greatly triggered ferroptosis, along with free iron accumulation and enhanced lipid peroxidation. Epithelial to mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR) phosphorylation were also considerably restrained in NSCLC cells co-treated with FLD/DDP. Mechanistically, the combinative treatment significantly reduced DUSP26 expression in NSCLC cells. More studies showed that DUSP26 was strongly up-regulated in human NSCLC samples compared with the paired normal tissues, and high DUSP26 predicted poor overall survival rate among patients. Importantly, we found that DUSP26 suppression intensively reduced the proliferation, EMT process and pEGFR expression in NSCLC cells, whereas facilitated ROS production, DNA damage and cell death; however, opposite phenotype was observed in NSCLC cells over-expressing DUSP26. More importantly, DUSP26 over-expression completely abolished the anti-cancer function of FLD/DDP in NSCLC cells. Animal studies finally confirmed that FLD/DDP in combination efficiently reduced tumor growth and lung metastasis in mice with ameliorated side effects. In conclusion, all these data illustrated that FLD and DDP combinational treatment effectively restrained NSCLC progression, and thus can be served as a promising therapeutic strategy.
非小细胞肺癌（NSCLC）是全球最常被诊断出的癌症之一，有效治疗方法有限。顺铂（DDP）作为一线治疗药物，一直是NSCLC治疗中联合其他药物的化疗药物的中流砥柱。然而，基于DDP的治疗由于化疗耐药性和不良反应的频繁发生而受到限制。在此，有必要找到一种毒性更小的更有效的治疗方法。法尼达莫尔（FLD）是一种嘧啶并嘧啶化合物，具有抗癌活性。在本研究中，我们发现FLD能强烈促进DDP的细胞毒性，并显著降低IC值以抑制NSCLC细胞的增殖。此外，FLD与DDP联合显著诱导G2/M期细胞周期阻滞、DNA损伤和线粒体凋亡，这主要是通过诱导活性氧（ROS）实现的。此外，FLD/DDP联合极大地引发了铁死亡，伴随着游离铁的积累和脂质过氧化的增强。在与FLD/DDP共同处理的NSCLC细胞中，上皮-间质转化（EMT）和表皮生长因子受体（EGFR）磷酸化也受到显著抑制。机制上，联合治疗显著降低了NSCLC细胞中DUSP26的表达。更多研究表明，与配对的正常组织相比，人NSCLC样本中DUSP26强烈上调，高DUSP26预示着患者的总生存率较差。重要的是，我们发现抑制DUSP26能强烈降低NSCLC细胞的增殖、EMT过程和pEGFR表达，同时促进ROS产生、DNA损伤和细胞死亡；然而，在过表达DUSP26的NSCLC细胞中观察到相反的表型。更重要的是，DUSP26过表达完全消除了FLD/DDP在NSCLC细胞中的抗癌功能。动物研究最终证实，FLD/DDP联合有效地减少了小鼠的肿瘤生长和肺转移，且副作用有所改善。总之，所有这些数据表明，FLD与DDP联合治疗有效地抑制了NSCLC的进展，并因此可作为一种有前景的治疗策略。
