title: Iron chelators in photodynamic therapy revisited: synergistic effect by novel highly active thiosemicarbazones.
abstract: In photodynamic therapy (PDT), a noninvasive anticancer treatment, visible light, is used as a magic bullet selectively destroying cancer cells by a photosensitizer that is nontoxic in the dark. Protoporphyrin IX (PpIX) is a natural photosensitizer synthesized in the cell, which is also a chelating agent that if bonded to Fe(2+) forms heme, a central component of hemoglobin. Therefore, xenobiotic iron chelators can disturb iron homeostasis, increasing the accumulation of PpIX, obstructing the last step of heme biosynthesis, and enhancing PDT efficiency. However, the attempts to use this promising idea have not proved to be hugely successful. Herein, we revisited this issue by analyzing the application of iron chelators highly toxic in the dark, which should have higher Fe(2+) affinity than the nontoxic chelators used so far. We have designed and prepared thiosemicarbazones (TSC) with the highest dark cellular cytotoxicity among TSCs ever reported. We demonstrate that compound 2 exerts powerful PDT enhancement when used in combination with 5-aminolevulinic acid (ALA), a precursor of PpIX.
authors.affiliation: Institute of Chemistry, University of Silesia , Szkolna 9, PL-40-006 Katowice, Poland ; Institute of Physics, University of Silesia , Uniwersytecka 4, PL-40-007 Katowice, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Mrozek-Wilczkiewicz
authors.affiliation: Institute of Chemistry, University of Silesia , Szkolna 9, PL-40-006 Katowice, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Serda
authors.affiliation: Institute of Chemistry, University of Silesia , Szkolna 9, PL-40-006 Katowice, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Musiol
authors.affiliation: Institute of Chemistry, University of Silesia , Szkolna 9, PL-40-006 Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Malecki
authors.affiliation: Institute of Physics, University of Silesia , Uniwersytecka 4, PL-40-007 Katowice, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szurko
authors.affiliation: Center of Biostructure Research, Medical University of Warsaw , Banacha 1a, PL-02-097 Warsaw, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Center of Biostructure Research, Medical University of Warsaw , Banacha 1a, PL-02-097 Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
authors.affiliation: Institute of Physics, University of Silesia , Uniwersytecka 4, PL-40-007 Katowice, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Ratuszna
authors.affiliation: Institute of Chemistry, University of Silesia , Szkolna 9, PL-40-006 Katowice, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Polanski
keywords: Photodynamic therapy; protoporphyrin IX; reactive oxygen species; thiosemicarbazones; triapine