Green Chemistry and Process Enhancement Technology, National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Huaiyin Institute of Technology, Huai'an, 223003, China.
Green Chemistry and Process Enhancement Technology, National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Huaiyin Institute of Technology, Huai'an, 223003, China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China.
Eur J Med Chem. 2024 Jan 5;263:115968. doi: 10.1016/j.ejmech.2023.115968. Epub 2023 Nov 19.
Platinum-based chemotherapeutics are widely used for cancer treatment but are frequently limited because of dosage-dependent side effects and drug resistance. To attenuate these drawbacks, a series of novel platinum(IV) prodrugs (15a-18c) were synthesized and evaluated for anti-cancer activity. Among them, 17a demonstrated superior anti-proliferative activity compared with oxaliplatin (OXA) in the cisplatin-resistant lung cancer cell line A549/CDDP and OXA-resistant colon cancer cell line HCT-116/OXA but showed a lower cytotoxic effect toward human normal cell lines HUVEC and L02. Mechanistic investigations suggested that 17a efficiently enhanced intracellular platinum accumulation, induced DNA damage, disturbed the homeostasis of intracellular reactive oxygen molecules and mitochondrial membrane potential, and thereby activated the mitochondrion-dependent apoptosis pathway. Moreover, 17a significantly induced ferroptosis in HCT-116/OXA via triggering the accumulation of lipid peroxides, disrupting iron homeostasis, and inhibiting solute carrier family 7 member 11 and glutathione peroxidase 4 axial pathway transduction by inhibiting the expression of the phosphorylated signal transducer and activator of transcription 3 and nuclear factor erythroid 2-related factor 2. Moreover, 17a exerted remarkable in vivo antitumor efficacy in the HCT-116/OXA xenograft models but showed attenuated toxicity. These results indicated that these novel platinum(IV) complexes provided an alternative strategy to develop novel platinum-based antineoplastic agents for cancer treatment.
铂类化疗药物被广泛用于癌症治疗，但由于剂量依赖性副作用和耐药性，其应用受到限制。为了减轻这些缺点，我们合成了一系列新型铂（IV）前药（15a-18c），并对其抗癌活性进行了评价。其中，17a 在顺铂耐药的肺癌细胞系 A549/CDDP 和奥沙利铂耐药的结肠癌细胞系 HCT-116/OXA 中表现出比奥沙利铂（OXA）更强的抗增殖活性，但对人正常细胞系 HUVEC 和 L02 的细胞毒性较低。机制研究表明，17a 能够有效增强细胞内铂的积累，诱导 DNA 损伤，扰乱细胞内活性氧分子和线粒体膜电位的平衡，从而激活线粒体依赖性细胞凋亡途径。此外，17a 通过触发脂质过氧化物的积累、破坏铁平衡、抑制溶质载体家族 7 成员 11 和谷胱甘肽过氧化物酶 4 轴通路的转导（通过抑制磷酸化信号转导和转录激活因子 3 和核因子红细胞 2 相关因子 2 的表达），显著诱导 HCT-116/OXA 中的铁死亡。此外，17a 在 HCT-116/OXA 异种移植模型中表现出显著的体内抗肿瘤疗效，但毒性降低。这些结果表明，这些新型铂（IV）配合物为开发新型铂类抗肿瘤药物治疗癌症提供了一种替代策略。
