Novel tacrine platinum(II) complexes display high anticancer activity via inhibition of telomerase activity, dysfunction of mitochondria, and activation of the p53 signaling pathway
| Autor: | Yan-Cheng Liu, Peng-Fei Yao, Ming-Xiong Tan, Dong-Mei Luo, Bi-Qun Zou, Hong Liang, Qi-Pin Qin, Zhen-Feng Wang, Shu-Long Wang |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Telomerase Cell cycle checkpoint Organoplatinum Compounds Cyclin A Antineoplastic Agents Apoptosis Mice 03 medical and health sciences Cell Line Tumor Neoplasms Drug Discovery medicine Animals Humans Cytotoxicity IC50 Pharmacology biology Chemistry Cell Cycle Organic Chemistry Hep G2 Cells General Medicine Molecular biology Mitochondria 030104 developmental biology Tacrine Cancer cell biology.protein Tumor Suppressor Protein p53 Signal Transduction medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 158:106-122 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.09.008 |
| Popis: | In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH3OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4′-dimethyl-2,2′-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1 Pt7 exhibited cytotoxic activity against the tested NCI H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug. |
| Databáze: | OpenAIRE |
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