title: Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells.
abstract: BACKGROUND
  Ovarian cancer is the seventh-most common cancer amongst women and the most deadly gynecologic cancer. Cisplatin based drugs are used in first line therapy, but resistance represents a major obstacle for successful treatment. In this study, we investigated the anticancer effects and mechanism of action of three titanocene difluorides, two bearing a pendant carbohydrate moiety (α-D-ribofuranos-5-yl) on their periphery and one without any substitution.
  
  
  RESULTS
  The efficacy of these compounds on ovarian cancer cell lines was evaluated in relation to their particular chemical structure and compared with cisplatin as the most common treatment modality for this type of cancer. The typical mechanism of cisplatin action involves DNA damage, activation of p53 protein and induction of cell death, as previously described for titanium ions. Nevertheless, our data indicate that the effect of titanocene difluoride derivatives is mediated via the endoplasmic reticulum stress pathway and autophagy.
  
  
  CONCLUSIONS
  We anticipate that the presence of substituents on cyclopentadienyl ring(s) might play an important role in modulation of the activity of particular compounds. Titanocene difluorides exert comparable cytotoxic activity as cisplatin and are more efficient in cisplatin-resistant cell lines. Our results suggest potential utilization of these compounds especially in the treatment of cisplatin-resistant tumor cells.
authors.affiliation: Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Koubkova
authors.affiliation: Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
authors.forename: Rostislav
authors.initials: R
authors.lastname: Vyzula
authors.affiliation: Institute of Chemical Process Fundamentals, Academy of Sciences of the Czech Republic, v.v.i., Rozvojova 135, 165 02, Prague 6, Czech Republic.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Karban
authors.affiliation: J. Heyrovsky Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Dolejskova 2155/3, 182 23, Prague 8, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Pinkas
authors.affiliation: Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Ondrouskova
authors.affiliation: Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojtesek
authors.affiliation: Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic. hrstka@mou.cz.
authors.forename: Roman
authors.initials: R
authors.lastname: Hrstka
mesh_terms: D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D006801:Humans; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D009942:Organometallic Compounds; D016159:Tumor Suppressor Protein p53; C406884:titanocene
keywords: Cisplatin; Cytotoxicity; Organometallic compounds; Ovarian cancer; Titanocene