In vitro evaluation of the enantiomeric R- and S-1,1′-binaphthyl-2,2′-diaminodichlorido–Pt(ii) complexes in human Burkitt lymphoma cells: emphasis on cellular accumulation, cytotoxicity, DNA binding, and ability to induce apoptosis

Abstract

The aim of this project is to gain insights into the uptake and cellular actions of the enantiomeric R- and S-1,1′-binaphthyl-2,2′-diaminodichlorido–Pt(II) complexes (R- and S-[Pt(DABN)Cl₂]) in the cisplatin-sensitive human Burkitt lymphoma cell line (Gumbus, IC₅₀: 1.3 ± 0.2 μM) and its cisplatin-resistant sub-line (CDDPrGB, IC₅₀: 6.6 ± 1.2 μM). The cellular uptakes of R- and S-[Pt(DABN)Cl₂] are ca. 4-fold higher than cisplatin, and involve a transport mechanism independent of the volume-sensitive, organic anion-channel complex, which facilitates cisplatin accumulation. The cisplatin-resistant CDDPrGB cells are not cross-resistant to either S- or R-[Pt(DABN)Cl₂]. We also find that even though R-[Pt(DABN)Cl₂] has a higher maximal cellular uptake and binds at higher levels to calf-thymus DNA than S-[Pt(DABN)Cl₂], it appears that S-[Pt(DABN)Cl₂] is more cytotoxic for Gumbus (IC₅₀: 0.4 ± 0.1 μM) compared to R-[Pt(DABN)Cl₂] (IC₅₀: 0.7 ± 0.3 μM). The cellular action of R- and S-[Pt(DABN)Cl₂] involves G0/G1 cell cycle arrest and cell death involving the extrinsic and intrinsic apoptotic pathways.