Cellular responses induced by Cu(II) quinolinonato complexes in human tumor and hepatic cells

Chemistry Central Journal

Zdeněk Trávníček³  Ján Vančo³  Jan Hošek³  Roman Buchtík²  Zdeněk Dvořák¹ 

[1] Department of Cell Biology and Genetics, Regional Centre of Advanced Technologies and Materials, Palacký University, Šlechtitelů 11, Olomouc, CZ–783 71, Czech Republic

[2] Department of Inorganic Chemistry, Palacký University, 17. listopadu 1192/12, Olomouc, CZ–771 46, Czech Republic

[3] Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Palacký University, 17. listopadu 1192/12, Olomouc, CZ–771 46, Czech Republic

关键词: Quinolinone derivatives;    Inflammatory response;    Gene reporter assay;    Hepatotoxicity;    In vitro cytotoxicity;    Copper(II) complexes;   

Others  :  787995
DOI  :  10.1186/1752-153X-6-160

 received in 2012-10-17, accepted in 2012-12-18,  发布年份 2012

【 摘 要 】

Background

Inspired by the unprecedented historical success of cisplatin, one of the most important research directions in bioinorganic and medicinal chemistry is dedicated to the development of new anticancer compounds with the potential to surpass it in antitumor activity, while having lower unwanted side-effects. Therefore, a series of copper(II) mixed-ligand complexes of the type [Cu(qui)(L)]Y · xH₂O (1–6), where Hqui = 2-phenyl-3-hydroxy-4(1H)-quinolinone, Y = NO₃ (1, 3, 5) or BF₄ (2, 4, 6), and L = 1,10-phenanthroline (phen) (1, 2), 5-methyl-1,10-phenanthroline (mphen) (3, 4) and bathophenanthroline (bphen) (5, 6), was studied for their in vitro cytotoxicity against several human cancer cell lines (A549 lung carcinoma, HeLa cervix epitheloid carcinoma, G361 melanoma cells, A2780 ovarian carcinoma, A2780cis cisplatin-resistant ovarian carcinoma, LNCaP androgen-sensitive prostate adenocarcinoma and THP-1 monocytic leukemia).

Results

The tested complexes displayed a stronger cytotoxic effect against all the cancer cells as compared to cisplatin. The highest cytotoxicity was found for the complexes 4 (IC₅₀ = 0.36 ± 0.05 μM and 0.56 ± 0.15 μM), 5 (IC₅₀ = 0.66 ± 0.07 μM and 0.73 ± 0.08 μM) and 6 (IC₅₀ = 0.57 ± 0.11 μM and 0.70 ± 0.20 μM) against A2780, and A2780cis respectively, as compared with the values of 12.0 ± 0.8 μM and 27.0 ± 4.6 μM determined for cisplatin. Moreover, the tested complexes were much less cytotoxic to primary human hepatocytes than to the cancer cells. The complexes 5 and 6 exhibited significantly high ability to modulate secretion of the pro-inflammatory cytokines TNF-α (2873 ± 238 pg/mL and 3284 ± 139 pg/mL for 5, and 6 respectively) and IL-1β (1177 ± 128 pg/mL and 1087 ± 101 pg/mL for 5, and 6 respectively) tested on the lipopolysaccharide (LPS)-stimulated THP-1 cells as compared with the values of 1173 ± 85 pg/mL and 118.5 ± 4.8 pg/mL found for the commercially used anti-inflammatory drug prednisone. The ability of the tested complexes to interact with sulfur-containing biomolecules (cysteine and reduced glutathione) at physiological levels was proved by electrospray-ionization mass spectrometry.

Conclusions

Overall positive results of the biological activity studies revealed that the presented complexes may represent good candidates for non-platinum anticancer drugs, however, we are aware of the fact that further and deeper studies mainly in relation to the elucidation of their mechanisms of antiproliferative action will be necessary.

【 授权许可】

   
2012 Travnicek et al.; licensee Chemistry Central Ltd.

【 图 表 】

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