Selective photodynamic inactivation of a multidrug transporter by a cationic photosensitising agent.
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.
Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201.
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003515:Cycloleucine / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D007941:Leukemia P388 / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010100:Oxygen / Q000378:metabolism; D010778:Photochemotherapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D026082:Singlet Oxygen; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D012235:Rhodamines; D003515:Cycloleucine; D026082:Singlet Oxygen; D020112:Rhodamine 123; D004317:Doxorubicin; D010100:Oxygen; D003630:Daunorubicin