Polyamine-Based Pt(IV) Prodrugs as Substrates for Polyamine Transporters Preferentially Accumulate in Cancer Metastases as DNA and Polyamine Metabolism Dual-Targeted Antimetastatic Agents
| Autor: | Shudi Guo, Qi Ma, Kai Feng, Linrong Li, Jianing Liu, Chaojie Wang, Yingguang Li, Hanfang Liu, Jing Ma, Xiao Zhang, Songqiang Xie, Sitong Liu, Peng George Wang, Zhuoqing Xi, Kexin Yue |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Lung Neoplasms
Mice Nude Antineoplastic Agents Apoptosis Breast Neoplasms 01 natural sciences Metastasis 03 medical and health sciences chemistry.chemical_compound Mice In vivo Drug Discovery medicine Polyamines Tumor Cells Cultured Animals Humans Prodrugs 030304 developmental biology Cell Proliferation Cisplatin 0303 health sciences Mice Inbred BALB C Oxidoreductases Acting on CH-NH Group Donors Cell growth Biological Transport DNA Prodrug medicine.disease Xenograft Model Antitumor Assays 0104 chemical sciences Oxaliplatin Gene Expression Regulation Neoplastic 010404 medicinal & biomolecular chemistry chemistry Drug Resistance Neoplasm Cancer research Molecular Medicine Female Polyamine medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 62(24) |
| ISSN: | 1520-4804 |
| Popis: | Diverse platinum drug candidates have been designed to improve inhibitory potency and overcome resistance for orthotopic tumors. However, the antimetastatic properties have rarely been reported. We herein report that homospermidineplatin (4a), a polyamine-Pt(IV) prodrug, can potently inhibit tumor growth in situ and reverse cisplatin resistance as expected, and more importantly, 4a displays remarkably elevated antimetastatic activity in vivo (65.7%), compared to those of cisplatin (27.0%) and oxaliplatin (19.6%). The underlying molecular mechanism indicates that in addition to targeting nuclear DNA, 4a can modulate polyamine metabolism and function in a manner different from that of cisplatin. By upregulating SSAT and PAO, 4a downregulates the concentrations of Put, Spd, and Spm, which favors the suppression of fast-growing tumor cells. Moreover, the p53/SSAT/β-catenin and PAO/ROS/GSH/GSH-Px pathways are involved in the inhibition of 4a-induced tumor metastasis. Our study implies a promising strategy for the design of platinum drugs for the treatment of terminal cancer. |
| Databáze: | OpenAIRE |
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