Cytotoxic activity and cellular processing in human ovarian carcinoma cell lines of a new platinum(II) compound containing a fluorescent substituted propylene diamine ligand

Patricia Marqués-Gallego , Hans Den Dulk , Jaap Brouwer , Stefania Tanase , Ilpo Mutikainen , Urho Turpeinen , Jan Reedijk

A new fluorescent platinum(II) compound containing the N,N′-bis-(anthracen-9-ylmethyl)propane-1,3-diamine as a carrier ligand has been designed, synthesized and characterized. High cytotoxic activity of -[Pt(bapda)Cl] is observed in A2780 and A2780R cells (human ovarian carcinoma sensitive and cisplatin-resistant, respectively). Nevertheless, cross-resistance to platinum from -[Pt(bapda)Cl] in the A2780R cells was found. To study the role of GSH towards inactivation of -[Pt(bapda)Cl], GSH-depleted and non-depleted A2780R cells were used in several studies. The results suggest that -[Pt(bapda)Cl] is not susceptible to the inactivation by GSH. Cellular processing of bapda and -[Pt(bapda)Cl] was followed using fluorescence microscopy in the A2780, the A2780R and GSH-depleted A2780R cells. Interestingly, differences in the cellular processing followed by fluorescence microscopy between normal and GSH-depleted A2780R cells have been observed for the carrier ligand. Sequestration of these compounds in acidic lysosomes is visible after incubation in most cases, and no fluorescence was observed in the nucleus. Interaction of -[Pt(bapda)Cl] with calf thymus DNA strongly suggests that the this new platinum(II) compound intercalates between the DNA base pairs. Additionally, the reaction of -[Pt(bapda)Cl] with 9-ethylguanine appears to be very slow, as studied by H and Pt-NMR spectroscopy.

Mots clés: bapda; MTT; 9-EtG; GSH; L-BSO; pEC values; RF; PBS; Cytotoxic activity; Fluorescence microscopy; Nucleobases; Platinum resistance; Glutathione

Patricia Marqués-Gallego, Hans Den Dulk, Jaap Brouwer, Stefania Tanase, Ilpo Mutikainen, et al.. Cytotoxic activity and cellular processing in human ovarian carcinoma cell lines of a new platinum(II) compound containing a fluorescent substituted propylene diamine ligand. Biochemical Pharmacology, 2009, 78 (4), pp.365. ⟨10.1016/j.bcp.2009.04.027⟩. ⟨hal-00493522⟩