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Differences in the cellular response and signaling pathways between cisplatin and monodentate organometallic Ru(II) antitumor complexes containing a terphenyl ligand
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Kisova, Anna, Zerzankova, Lenka, Habtemariam, Abraha, Sadler, P. J., Brabec, V. (Viktor) and Kasparkova, Jana (2011) Differences in the cellular response and signaling pathways between cisplatin and monodentate organometallic Ru(II) antitumor complexes containing a terphenyl ligand. Molecular Pharmaceutics, Vol.8 (No.3). pp. 949-957. doi:10.1021/mp200105d ISSN 1543-8384.
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Official URL: http://dx.doi.org/10.1021/mp200105d
Abstract
The new monofunctional Ru(II)-arene complex [(η6-arene)Ru(II)(en)Cl]+, where en = 1,2-diaminoethane and the arene is para-terphenyl (complex 1) exhibits promising cytotoxic effects in human tumor cells including those resistant to conventional cisplatin (J. Med. Chem.2008, 51, 5310). The present study is focused on the cellular pharmacology of 1 to elucidate more deeply the mechanisms underlying its antitumor effects. We have identified several cellular mechanisms induced by 1 in human ovarian carcinoma cells, including inhibition of DNA synthesis, overexpression and activation of p53, expression of proapoptotic proteins p21WAF1 and Bax, G0/G1 arrest, and nuclear fragmentation as a result of apoptotic, and, to a much lower extent, also necrotic processes. Thus, 1 inhibits growth of the cancer cells through induction of apoptotic cell death and G0/G1 cell cycle arrest. Further investigations have shown that 1 induces apoptosis by regulating the expression of Bcl-2 family proteins. There were significant differences in cellular responses to the treatment with 1 and with conventional cisplatin, particularly in the kinetics and the extent of these responses. In addition, the distinct p53 activation profile of 1 compared with cisplatin provides an explanation for the activity of this ruthenium drug against cisplatin-resistant cells. Hence complex 1 may provide an alternative therapy in patients with acquired cisplatin resistance, particularly with respect to its very low mutagenicity and different mode of action compared to platinum antitumor drugs in clinical use.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
| Library of Congress Subject Headings (LCSH): | Ruthenium compounds -- Therapeutic use, p53 protein, Antineoplastic agents, Cell cycle, Mutagenicity testing, Apoptosis | ||||
| Journal or Publication Title: | Molecular Pharmaceutics | ||||
| Publisher: | American Chemical Society | ||||
| ISSN: | 1543-8384 | ||||
| Official Date: | 2011 | ||||
| Dates: |
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| Volume: | Vol.8 | ||||
| Number: | No.3 | ||||
| Page Range: | pp. 949-957 | ||||
| DOI: | 10.1021/mp200105d | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Czech Republic. Ministerstvo školství, mládeže a tělovýchovy [Czech Republic. Ministry of Education, Youth, and Sports], Akademie věd České republiky [Academy of Sciences of the Czech Republic] (ASCR), Grantová agentura České republiky [Czech Science Foundation] (GACR), European Regional Development Fund (ERDF), European Research Council (ERC), Advantage West Midlands (AWM) | ||||
| Grant number: | LC06030 (MSMT), OC09018 (MSMT), M200040901 (ASCR), P303/10/P047 (GACR), 301/09/H004 (GACR), 247450 (ERC) |
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