Novel Copper Complexes That Inhibit the Proteasome and Trigger Apoptosis in Triple-Negative Breast Cancer Cells
| Autor: | Zi-Bo Yang, Luyao Wang, Lin-Lin Dai, Yunhui Hu, Xiumei Zhao, Shuang Zhi, Ernesto Yagüe, Na Zhang, Dong-Dong Li |
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| Přispěvatelé: | Breast Cancer Care & Breast Cancer Now |
| Rok vydání: | 2019 |
| Předmět: |
Programmed cell death
0304 Medicinal and Biomolecular Chemistry 010405 organic chemistry Chemistry Cell growth Organic Chemistry 0305 Organic Chemistry 01 natural sciences Biochemistry Molecular biology 0104 chemical sciences 010404 medicinal & biomolecular chemistry Proteasome Docking (molecular) Apoptosis Cell culture Drug Discovery 1115 Pharmacology and Pharmaceutical Sciences Cytotoxicity Triple-negative breast cancer |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.9b00284 |
| Popis: | [Image: see text] Five innovative ternary copper(II) complexes [Cu(OH-PIP)(Phe)Cl](1), [Cu(OH-PIP)(Gly)(H(2)O)]NO(3)·2H(2)O (2), [Cu(OH-PIP)(Ala)(Cl)]·H(2)O (3), [Cu(OH-PIP)(Met)]PF(6)·2H(2)O (4), and [Cu(OH-PIP)(Gln)(H(2)O)](Cl)·3H(2)O (5) have been synthesized and characterized by infrared spectroscopy, elemental analysis, and single crystal X-ray diffraction analysis. X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration. The complexes have been screened for cytotoxicity against human breast cancer cell lines MCF-7, MDA-MB-231, and CAL-51. The best anticancer activity is obtained with triple-negative breast cancer CAL-51 and MDA-MB-231 cell lines, with IC(50) values in the range of 0.082–0.69 μM. Importantly, the copper compounds were more effective than carboplatin at triggering cell death. Mechanistically, the complexes inhibit proteasomal chymotrypsin-like activity, and docking studies reveal their 20S proteasome binding sites. As a consequence, they cause the accumulation of ubiquitinated proteins, inhibit cell proliferation, and induce apoptosis. In addition, these copper complexes decrease the stemness of triple-negative breast cancer cells and have synergistic effects with CBP on TNBC cells, indicating their great potential as a novel therapy for triple-negative breast cancer. |
| Databáze: | OpenAIRE |
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