Wang Meng, Li Guimei, Xu Nan, Wang Lang, Cai Jinyuan, Huang Rizhen, Yang Yong, Chen Guiping, Liu Zhikun, Zhang Ye, Wang Hengshan, Huang Xiaochao
National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China.
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center For Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China.
J Med Chem. 2025 Mar 13;68(5):5597-5615. doi: 10.1021/acs.jmedchem.4c02840. Epub 2025 Feb 20.
Acquired resistance in cancer remains a significant challenge in oncology, posing obstacles to the efficacy of diverse therapeutic approaches. The nuclear factor-kappa B (NF-κB) signaling pathway plays an important role in the development of drug resistance in tumor cells. Herein, we employed NF-κB inhibitors and cisplatin to synthesize multitarget Pt(IV) antitumor prodrugs. Among them, the antiproliferation activity of complex demonstrated a remarkable 146.92-time increase compared to cisplatin against A549/CDDP cells. Moreover, complex could effectively induce DNA damage, promote ROS generation, induce autophagy, trigger the mitochondrial apoptosis pathway, and suppress cell proliferation through the NF-κB signaling pathway. Furthermore, complex effectively downregulated the levels of VEGF and HIF-1α and exerted antiproliferative activity through the PI3K/AKT and STAT-3 pathway in A549/CDDP cells. Interestingly, complex showed a superior in vivo antitumor activity than cisplatin, , or their combination, suggesting its potential as a promising candidate for further drug development in lung cancer treatment.
癌症中的获得性耐药仍然是肿瘤学中的一个重大挑战，对多种治疗方法的疗效构成障碍。核因子-κB（NF-κB）信号通路在肿瘤细胞耐药性的发展中起重要作用。在此，我们使用NF-κB抑制剂和顺铂合成了多靶点铂（IV）抗肿瘤前药。其中，配合物对A549/CDDP细胞的抗增殖活性相比顺铂有显著的146.92倍增加。此外，配合物可有效诱导DNA损伤、促进活性氧生成、诱导自噬、触发线粒体凋亡途径，并通过NF-κB信号通路抑制细胞增殖。此外，配合物有效下调A549/CDDP细胞中VEGF和HIF-1α的水平，并通过PI3K/AKT和STAT-3途径发挥抗增殖活性。有趣的是，配合物在体内显示出比顺铂、或它们的组合更优越的抗肿瘤活性，表明其作为肺癌治疗中进一步药物开发的有前途候选者的潜力。
