title: Proapoptotic activity in vitro of two novel ruthenium(II) complexes with flavanone-based ligands that overcome cisplatin resistance in human bladder carcinoma cells.
abstract: In this study we examined their proapoptotic activity of cis-dichloridobis(3-imino-2-methoxyflavanone)ruthenium(II)3H(2)O (1) and cis-dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(II)2H(2)O (2) towards human bladder carcinoma cell line EJ and its cisplatin resistant subline EJcisR. On the basis of the experiments we carried out, it may be concluded, that: CDDP (cis-diamminedichloridoplatinum) resistance of EJcisR cells is probably based on partial loss of apoptotic pathway activating caspase-8 and increased resistance to DNA strand breaks and/or alkali-labile sites. Increased glutathione levels, as well as activity of P-gp transporter seems to be not relevant in this case. The proapoptotic activity of the ruthenium compounds is higher than that of cisplatin. Higher proapoptotic activity of 1 and 2 when compared to CDDP may be due to the presence of large, lipophilic flavanone-based ligands that may facilitate their trans-membrane transport and their redox activity. 1 and 2 induce apoptosis apparently in more than one way. Although caspase-8 activation and DNA strand breaks and/or alkali-labile sites are caused by the compounds, their ability to cause the oxidative stress in the cells may also participate in apoptosis induction.
authors.affiliation: Department of Bioinorganic Chemistry, Medical University, Muszynskiego 1, Lodz, Poland. maria.kasprzak@umed.lodz.pl
authors.forename: Maria M
authors.initials: MM
authors.lastname: Kasprzak
authors.forename: Leszek
authors.initials: L
authors.lastname: Szmigiero
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Zyner
authors.forename: Justyn
authors.initials: J
authors.lastname: Ochocki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D044950:Flavanones / Q000737:chemistry; D006801:Humans; D008024:Ligands; D018384:Oxidative Stress; D020112:Rhodamine 123 / Q000494:pharmacology; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D044950:Flavanones; D008024:Ligands; D017975:Ruthenium Compounds; C555408:dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(II); C555407:dichloridobis(3-imino-2-methoxyflavanone)ruthenium(II); D020112:Rhodamine 123; D053181:Caspase 8; D002945:Cisplatin; C028610:flavanone