title: Light-induced cytotoxicity after aminolevulinic acid treatment is mediated by heme and not by iron.
abstract: Photodynamic therapy (PDT) is a promising antitumor treatment strategy. However, effectiveness of PDT is limited due to an initiation of rescue responses in tumor cells, including the induction of heme oxygenase-1 (HO-1). Furthermore, the main sources of free radical production in PDT-induced oxidative stress are not clear. Here, human melanoma cells were loaded with the photosensitizer 5-aminolevulinic acid and exposed to non-thermal light of 420-800 nm at different doses. It was shown that inhibition of HO-1 activity by zinc protoporphyrin IX increased PDT-induced cytotoxicity in a dose-dependent manner. Interestingly, the cytotoxic effects were not diminished by the simultaneous application of the iron chelator desferrioxamine. Importantly, PDT together with non-toxic doses of hemin increased the number of dead cells. From these results can be concluded that heme but not iron act as the main source of free radicals in PDT treatment. This is supported by the fact that during PDT ferritin is readily up-regulated, able to bind excess iron formed by the HO-1 action. The combined treatment of photosensitizers with HO-1 inhibitors might increase the effectiveness of PDT in tumor treatment.
authors.affiliation: University of Hohenheim, Institute of Biological Chemistry and Nutrition, Stuttgart, Germany.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Breusing
authors.forename: Stefanie
authors.initials: S
authors.lastname: Grimm
authors.forename: Dagmar
authors.initials: D
authors.lastname: Mvondo
authors.forename: Andrea
authors.initials: A
authors.lastname: Flaccus
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Biesalski
authors.forename: Tilman
authors.initials: T
authors.lastname: Grune
mesh_terms: D000622:Aminolevulinic Acid / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D008027:Light; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000633:toxicity*; D011524:Protoporphyrins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007502:Iron Chelating Agents; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C017803:zinc protoporphyrin; D006418:Heme; D000622:Aminolevulinic Acid; D007501:Iron; D051547:Heme Oxygenase-1; D003676:Deferoxamine