title: Glycol porphyrin derivatives and temoporfin elicit resistance to photodynamic therapy by different mechanisms.
abstract: The development of drug resistance is a major problem which often occurs during anticancer chemotherapies. Photodynamic therapy (PDT) has been studied as an alternative treatment modality for drug-resistant tumors, however the question of resistance to PDT and potential cross-resistance with chemotherapy has yet to be fully answered. To investigate the mechanism of resistance to PDT, we developed an in vitro experimental model system in a mouse mammary carcinoma cell line 4T1. We used two ethylene glycol derivatives of tetraphenylporphyrin, and tetraphenylchlorin derivative, temoporfin, as photosensitizers (PS). PDT-resistant clones were obtained by exposure to a set concentration of PS followed by irradiation with increasing light doses. PDT resistance to soluble glycol porphyrins was mediated mainly by increased drug efflux through ABCB1 (P-glycoprotein) as we demonstrated by specific ABCB1 knockdown experiments, which in turn rescued the sensitivity of resistant cells to PDT. In contrast, resistance raised to temoporfin, which is generally more lipophilic than glycol porphyrins, elicited mechanism based on sequestration of the drug to lysosomes. The resistance that is acquired from a particular PS could be overcome by using a different PS, which is not susceptible to the same mechanism(s) of resistance. Elucidation of the underlying mechanisms in various types of resistance might facilitate improvements in PDT treatment design.
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Kralova
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.|Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Kolar
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Kahle
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.|Laboratory of Tumor Resistance, Institute of Biotechnology of the ASCR, v. v. i., BIOCEV, Vestec, Prague-West, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Truksa
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.|Laboratory of Tumor Resistance, Institute of Biotechnology of the ASCR, v. v. i., BIOCEV, Vestec, Prague-West, Czech Republic.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lettlova
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.|Division of Cell and Molecular Biology &Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Kamila
authors.initials: K
authors.lastname: Balusikova
authors.affiliation: CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Bartunek
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D055785:Gene Knockdown Techniques; D006018:Glycols / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008652:Mesoporphyrins / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D017239:Paclitaxel / Q000009:adverse effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000737:chemistry; D011166:Porphyrins / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005026:Ethylene Glycols; D006018:Glycols; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D011166:Porphyrins; C072269:temoporfin; D017239:Paclitaxel