Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells

• Published in: Investigational new drugs Vol. 33; no. 5; pp. 1123 - 1132
• Main Authors: Koubkova, Lucie, Vyzula, Rostislav, Karban, Jindrich, Pinkas, Jiri, Ondrouskova, Eva, Vojtesek, Borivoj, Hrstka, Roman
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2015; Springer Nature B.V
• Subjects: Autophagy - drug effects; Blotting, Western; Cancer therapies; Cell Cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Clinical trials; Cytotoxicity; DNA Damage - drug effects; Drugs; Endoplasmic reticulum; Female; Humans; Kinases; Laboratories; Medicine; Medicine & Public Health; Membranes; Oncology; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Oxidative Stress - drug effects; Penicillin; Pharmacology/Toxicology; Proteins; Short Report; Structure-Activity Relationship; Studies; Tumor Suppressor Protein p53 - biosynthesis; Czech Republic; Cytotoxicity; Titanocene; Cisplatin; Organometallic compounds; Ovarian cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-015-0274-y

Summary 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. Conclusion 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.