Poster Presentation 2014 International Biophysics Congress

Permeability and mechanism of transport of cisplatin across lipid membranes (#298)

Nasma Almansouri 1 , Ron Clarke 1
  1. University of Sydney, Camperdown, NSW, Australia

Cisplatin chemotherapy is the cornerstone of treatment of many cancers. This platinum complex reacts in vivo, binding to and causing crosslinking of DNA, which ultimately triggers apoptosis. Many mechanisms of cisplatin resistance have been proposed including changes in cellular uptake and efflux of the drug, increased detoxification of the drug, inhibition of apoptosis and increased DNA repair. The mechanism by which cisplatin enters cells is unknown. It has been generally supposed that cisplatin enters the cell largely through passive diffusion. However, other authors have reported that cisplatin may be actively transported via an amino acid transport system. The aim of this study was to evaluate the mechanism by which cisplatin enters cell membranes. Liposomes made of egg lethicin and dioleoyl-sn-glycero lecithin (DOPC) were used as model membranes to evaluate the permeation of cisplatin under physiological condition using a light scattering technique. The liposome size was characterized cryoelectronmicroscopy and dynamic light scattering. As cisplatin is not stable in pure water and dissociates to different metabolites, it was stabilized by adding NaCl in the range of 10-150 mM. It was found that the permeability of cisplatin increased with increasing chloride ion concentration. This suggests that cisplatin crosses cell membranes in a neutral form by a passive diffusion mechanism rather than by a protein transporter. Once inside a cell the low chloride ion concentration causes choride dissociation and conversion of cisplatin into charged forms with lower membrane permeability, causing accumulation within the cytoplasm. Changes in cellular uptake of the cisplatin is thus not likely to contribute to the development of drug resistance.