Selective photodynamic inactivation of a multidrug transporter by a cationic photosensitising agent

Abstract

We have characterised sites of photodamage catalysed by the cationic photosensitiser tetrabromorhodamine 123, using P388 murine leukaemia cells and a subline (P388 ADR) which has a multidrug resistance phenotype and hyperexpresses mdr1 mRNA for P-glycoprotein. Fluorescence emission spectra were consistent with sensitiser localisation in hydrophobic regions of the P388 cell, and in more aqueous loci in P388 ADR. Subsequent irradiation resulted in photodamage to the P388 cells, resulting in loss of viability. In contrast, P388 ADR cells were unaffected except for an irreversible inhibition of P-glycoprotein, leading to enhanced accumulation of daunorubicin and rhodamine 123 and a corresponding increase in daunorubicin cytotoxicity. These results are consistent with the premise that substrates for P-glycoprotein are confined to membrane loci associated with the transporter, and indicate a very limited migration of cytotoxic photo-products in a cellular environment. © 1995 Stockton Press. All rights reserved.