title: Differences in the cellular response and signaling pathways between cisplatin and monodentate organometallic Ru(II) antitumor complexes containing a terphenyl ligand.
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 p21(WAF1) 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.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Kisova
authors.forename: Lenka
authors.initials: L
authors.lastname: Zerzankova
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D012428:Ruthenium / Q000737:chemistry* / Q000494:pharmacology*; D013730:Terphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D013730:Terphenyl Compounds; D016159:Tumor Suppressor Protein p53; D012428:Ruthenium; D002945:Cisplatin