Potentiation of photodynamic therapy by ursodeoxycholic acid.
Ursodeoxycholic acid (UDCA) protects cells from the apoptotic effects of hydrophobic bile acids and some other cytotoxic agents. We observed the opposite result when assessing the effects of UDCA on the apoptotic response to mitochondrial photodamage induced by photodynamic therapy (PDT). Two photosensitizers with predominantly mitochondrial specificity were used: a porphycene we have designated CPO; and the tin etiopurpurin SnET2. UDCA potentiated the loss of mitochondrial potential, release of cytochrome c into the cytosol, activation of caspase-3, and apoptotic cell death after irradiation of photosensitized murine leukemia L1210 or hepatoma 1c1c7 cells. These effects were not observed when UDCA was added after irradiation. Glyco-UDCA and tauro-UDCA, conjugated forms of UDCA that are formed in vivo, were as effective as UDCA in promoting PDT phototoxicity. Because UDCA does not act by enhancing intracellular accumulation of the photosensitizing agents used in this study, we propose that the mode of action of UDCA involves the sensitization of mitochondrial membranes to photodamage. UDCA is used currently in gastroenterology for several indications. The drug may offer a means for promoting the efficacy of PDT with minimal adverse effects.
Kessel
D
D
Department of Pharmacology and Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. dhkessel@med.wayne.edu
Caruso
J A
JA
Reiners
J J
JJ
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002756:Cholagogues and Choleretics / Q000627:therapeutic use; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D007425:Intracellular Membranes / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000528:radiation effects; D010778:Photochemotherapy; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D002756:Cholagogues and Choleretics; D003574:Cytochrome c Group; D014580:Ursodeoxycholic Acid; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases