title: Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells.
abstract: Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.
authors.affiliation: Institute of Biology and Ecology, Faculty of Science, P.J. Safárik University in Kosice, Moyzesova 11, 040 01, Kosice, Slovakia.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Jendzelovský
authors.forename: Jaromír
authors.initials: J
authors.lastname: Mikes
authors.forename: Ján
authors.initials: J
authors.lastname: Koval'
authors.forename: Karel
authors.initials: K
authors.lastname: Soucek
authors.forename: Jirina
authors.initials: J
authors.lastname: Procházková
authors.forename: Martin
authors.initials: M
authors.lastname: Kello
authors.forename: Veronika
authors.initials: V
authors.lastname: Sacková
authors.forename: Jirina
authors.initials: J
authors.lastname: Hofmanová
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.forename: Peter
authors.initials: P
authors.lastname: Fedorocko
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000873:Anthracenes; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D008027:Light; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000873:Anthracenes; D053148:Caspase 3; D053453:Caspase 9; D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010569:Perylene; D017319:Photosensitizing Agents; D011335:Proadifen; D017382:Reactive Oxygen Species; C116614:ABCG2 protein, human; C004965:hypericin; C421109:multidrug resistance-associated protein 1