Title
Cytotoxicity-boosting of kiteplatin by Pt(IV) prodrugs with axial benzoate ligands
Document Type
Article
Publication Date
2016
Department/School
Chemistry
Abstract
Kiteplatin, the neglected drug analogous of cisplatin but containing cis-1,4-DACH in place of the two ammines, has been recently reevaluated for its activity against cisplatin- and oxaliplatin-resistant tumors, in particular colo-rectal cancer. With the aim of further improving the pharmacological activity of this drug, Pt(IV) prodrugs were derived by addition of two, differently substituted, benzoate groups in axial positions (X-ray structure). The cytotoxic activity of both compounds resulted markedly potentiated reaching nanomolar concentration against a wide panel of human cancer cells. The ability of benzoate ligands to enhance the activity of kiteplatin most likely originates from their lipophilicity promoting a higher drug accumulation in cancer cells; however, it is to be noted that the increase in pharmacological effect is far greater than the increase in cellular uptake. Overcoming cisplatin- and oxaliplatin-resistance by kiteplatin derivatives appears to relate to the inability of membrane extrusion pumps to remove active Pt species from tumor cells.
Link to Published Version
Recommended Citation
Margiotta, N., Savino, S., Marzano, C., Pacifico, C., Hoeschele, J. D., Gandin, V., & Natile, G. (2016). Cytotoxicity-boosting of kiteplatin by Pt(IV) prodrugs with axial benzoate ligands. Journal of Inorganic Biochemistry, 160, 85–93. doi:10.1016/j.jinorgbio.2015.11.028