2. Academic Validation
  3. Novel Platinum(IV) complexes intervene oxaliplatin resistance in colon cancer via inducing ferroptosis and apoptosis

Novel Platinum(IV) complexes intervene oxaliplatin resistance in colon cancer via inducing ferroptosis and apoptosis

  • Eur J Med Chem. 2024 Jan 5:263:115968. doi: 10.1016/j.ejmech.2023.115968.
Zhikun Liu 1,  Jinyuan Cai 1,  Guiyang Jiang 1,  Meng Wang 2,  Chuang Wu 1,  Kangning Su 1,  Weiwei Hu 1,  Yaxian Huang 1,  Chunhao Yu 1,  Xiaochao Huang 3,  Guoxiu Cao 4,  Hengshan Wang 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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. Electronic address: [email protected].
  • 4 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. Electronic address: [email protected].
  • 5 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. Electronic address: [email protected].
PMID: 37995563 DOI: 10.1016/j.ejmech.2023.115968
Abstract

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.

Keywords

Ferroptosis inducer; Multi-functional antineoplastic; Overcoming oxaliplatin resistance; Platinum(IV) complexes.

Figures
Products