Cell cycle, apoptosis, cellular uptake and whole-transcriptome microarray gene expression analysis of HeLa cells treated with a ruthenium(II)-arene complex with an isoquinoline-3-carboxylic acid ligand
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2016
Authors
Jovanovic, Katarina K.Tanic, Miljana
Ivanovic, Ivanka
Gligorijević, Nevenka

Dojčinović, Biljana

Radulovic, Sinisa
Article (Published version)

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Show full item recordAbstract
Ruthenium(II)-arene complexes are promising drug candidates for the therapy of solid tumors. In previous work, seven new compounds of the general formula [Ru(eta(6)-p-cymene)(L1-7)Cl] were synthesized and characterized, of which the complex with L = isoquinoline-3-carboxylic acid (RuT7) was two times as active on HeLa cells compared to normal cell line MRC-5, as indicated by ICso values determined after 48 h of incubation (45.4 +/- 3.0 vs. 842 +/- 5.7 mu M, respectively). In the present study, cell cycle analysis of HeLa cells treated with RuT7 showed S phase arrest and an increase in sub-G1 population. The apoptotic potential of the title compound was confirmed with the Annexin V-FITC/PI assay together with a morphological evaluation of cells using fluorescent microscopy. Analysis of the intracellular accumulation of ruthenium showed 8.9 ng Ru/10(6) cells after 6 h of incubation. To gain further insight in the molecular mechanism of action of RuT7 on HeLa cells, a whole-transcriptome ...microarray gene expression analysis was performed. Analysis of functional categories and signaling and biochemical pathways associated with the response of HeLa cells to treatment with RuT7 showed that it leads the cells through the intrinsic (mitochondrial) apoptotic pathway, via indirect DNA damage due to the action of reactive oxygen species, and through direct DNA binding of RuT7. Statistical analysis for enrichment of gene sets associated with known drug-induced toxicities identified fewer associated toxicity profiles in RuT7-treated cells compared to cisplatin treatment. Altogether these results provide the basis for further development of RuT7 in animal and pre-clinical studies as a potential drug candidate.
Keywords:
Ruthenium(II) / Anticancer drugs / Apoptosis / HeLa / MicroarraySource:
Journal of Inorganic Biochemistry, 2016, 163, 362-373Publisher:
- Elsevier Science Inc, New York
Projects:
- Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors (RS-41026)
- Structure-properties relationships of natural and synthetic molecules and their metal complexes (RS-172017)
- Application of advanced oxidation processes and nanostructured oxide materials for the removal of pollutants from the environment, development and optimisation of instrumental techniques for efficiency monitoring (RS-172030)
DOI: 10.1016/j.jinorgbio.2016.04.011
ISSN: 0162-0134
PubMed: 27118029