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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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1984acc.pdf (1.416Mb)
Аутори
Jovanovic, Katarina K.
Tanic, Miljana
Ivanovic, Ivanka
Gligorijević, Nevenka
Dojčinović, Biljana
Radulovic, Sinisa
Чланак у часопису (Рецензирана верзија)
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Апстракт
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.

Кључне речи:
Ruthenium(II) / Anticancer drugs / Apoptosis / HeLa / Microarray
Извор:
Journal of Inorganic Biochemistry, 2016, 163, 362-373
Издавач:
  • Elsevier
Финансирање / пројекти:
  • Фармакодинамска и фармакогеномска испитивања новијих лекова у лечењу солидних тумора (RS-41026)
  • Корелација структуре и особина природних и синтетичких молекула и њихових комплекса са металима (RS-172017)
  • Примена унапређених оксидационих процеса и наноструктурисаних оксидних материјала за уклањање загађивача из животне средине, развој и оптимизација инструменталних техника за праћење ефикасности (RS-172030)
Напомена:
  • This is the peer-reviewed version of the article: Jovanovic KK, Tanic M, Ivanovic I, Gligorijević N, Dojčinović B, Radulovic S. 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. Journal of Inorganic Biochemistry. 2016;163:362-373, https://doi.org/10.1016/j.jinorgbio.2016.04.011
  • The published version: https://cer.ihtm.bg.ac.rs/handle/123456789/1984
Повезане информације:
  • Друга верзија
    https://cer.ihtm.bg.ac.rs/handle/123456789/1984

DOI: 10.1016/j.jinorgbio.2016.04.011

ISSN: 0162-0134

PubMed: 27118029

WoS: 000388546800039

Scopus: 2-s2.0-84964297949
[ Google Scholar ]
20
19
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/4386
Колекције
  • Radovi istraživača / Researchers' publications
Институција/група
IHTM
TY  - JOUR
AU  - Jovanovic, Katarina K.
AU  - Tanic, Miljana
AU  - Ivanovic, Ivanka
AU  - Gligorijević, Nevenka
AU  - Dojčinović, Biljana
AU  - Radulovic, Sinisa
PY  - 2016
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/4386
AB  - 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.
PB  - Elsevier
T2  - Journal of Inorganic Biochemistry
T1  - 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
VL  - 163
SP  - 362
EP  - 373
DO  - 10.1016/j.jinorgbio.2016.04.011
ER  - 
@article{
author = "Jovanovic, Katarina K. and Tanic, Miljana and Ivanovic, Ivanka and Gligorijević, Nevenka and Dojčinović, Biljana and Radulovic, Sinisa",
year = "2016",
abstract = "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.",
publisher = "Elsevier",
journal = "Journal of Inorganic Biochemistry",
title = "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",
volume = "163",
pages = "362-373",
doi = "10.1016/j.jinorgbio.2016.04.011"
}
Jovanovic, K. K., Tanic, M., Ivanovic, I., Gligorijević, N., Dojčinović, B.,& Radulovic, S.. (2016). 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. in Journal of Inorganic Biochemistry
Elsevier., 163, 362-373.
https://doi.org/10.1016/j.jinorgbio.2016.04.011
Jovanovic KK, Tanic M, Ivanovic I, Gligorijević N, Dojčinović B, Radulovic S. 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. in Journal of Inorganic Biochemistry. 2016;163:362-373.
doi:10.1016/j.jinorgbio.2016.04.011 .
Jovanovic, Katarina K., Tanic, Miljana, Ivanovic, Ivanka, Gligorijević, Nevenka, Dojčinović, Biljana, Radulovic, Sinisa, "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" in Journal of Inorganic Biochemistry, 163 (2016):362-373,
https://doi.org/10.1016/j.jinorgbio.2016.04.011 . .

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