Ni(ii ), Cu(ii ) and Zn(ii ) complexes with the 1-trifluoroethoxyl-2,9,10-trimethoxy-7-oxoaporphine ligand simultaneously target microtubules and mitochondria for cancer therapy
| Autor: | Cheng Hou, Hong Liang, Zu-Yu Mo, Gui-Fa Su, Zhen-Feng Chen, Yin Chen, Lan-Shan Liao |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Cell cycle checkpoint Mitochondrion Ligand (biochemistry) In vitro Inorganic Chemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry Microtubule Apoptosis 030220 oncology & carcinogenesis Biophysics Growth inhibition Intracellular 030304 developmental biology |
| Zdroj: | Inorganic Chemistry Frontiers. 8:2225-2247 |
| ISSN: | 2052-1553 |
| DOI: | 10.1039/d0qi01463j |
| Popis: | Metal complexes of [NiL2(NO3)2] (1), [CuL2(NO3)2] (2) and [ZnL2(NO3)2] (3) with the 1-trifluoroethoxyl-2,9,10-trimethoxy-7-oxoaporphine (L) ligand were synthesized. We discovered that complexes 1–3 exhibited considerable anticancer activity in vitro via simultaneously targeting microtubules and mitochondria. Complexes 1–3 impaired mitochondrial bioenergetic function by causing ATP depletion and mitochondrial membrane depolarization. They also triggered excessive generation of intracellular ROS and Ca2+, activated caspase-3 and caspase-9, and triggered mitochondria-dependent apoptosis pathways. In addition, complexes 1–3 were shown by SPR and CETSA assays to have a good binding affinity for β-tubulin. Tubulin polymerization analysis suggested that complexes 1–3 promoted tubulin polymerization into microtubules, and disrupted the microtubule cytoskeleton network, which caused cell cycle arrest in the G2/M phase. Complexes 1–3 ultimately activated a strongly apoptotic response. Complexes 1 and 2 displayed high cancer growth inhibition efficacy in mice bearing T-24 xenografts, and had a good in vivo safety profile. Complexes 1–3 have the potential to become anticancer agents through targeting microtubule and mitochondria. |
| Databáze: | OpenAIRE |
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