Titanocene Y and Vanadocene Y: Platinum Resistance-Breaking Cytotoxic and DNA-Targeting Anticancer Drug Candidates
Ralf A. Hilger,
Platinum-based chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin are used to treat a broad range of malignant diseases. Their efficacies in most cancers are limited by the development of resistance. There are multiple factors that contribute to platinum resistance but alterations of DNA repair processes have been known for some time to be important in mediating resistance. The two anticancer drug candidates Titanocene Y and Vanadocene Y (bis- [(p-methoxybenzyl)cyclopentadienyl] titanium(IV) and vanadium(IV) dichloride) were investigated against the wild-type as well as the platinum-resistant human colon cancer cells HCT-8. Both metallocene drugs were able to break the cisplatin-, carboplatin- and oxaliplatin-resistance in the newly generated corresponding sub-clones of the HCT-8 cells by showing resistance factors ranging from 1.0 - 1.2 for Titanocene Y and 1.1 - 1.6 for Vanadocene Y. In addition, drug uptake and DNA assays were performed using HCT-8 cells again and ICP-MS as the analytical method. High DNA-adduct levels were obtained at IC50 concentrations of Titanocene as well as Vanadocene, which indicates that DNA is a target for these metallocene drugs leading to apoptosis in platinum-resistant HCT-8 cells.
Keywords: Anticancer drugs, Bioorganometallic Vanadocene, Colon cancer, DNA binding, Platinum-resistance, Titanocene, DNA, IC50 concentrations, ICP-MS, HCT-8 cells, TiCl4, metallocene dichloride derivatives, cross-resistance, platinum-based drugs, wild type, HRT-18
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