title: Roles of porphyrin and iron metabolisms in the δ-aminolevulinic acid (ALA)-induced accumulation of protoporphyrin and photodamage of tumor cells.
abstract: δ-Aminolevulinic acid (ALA)-induced porphyrin accumulation is widely used in the treatment of cancer, as photodynamic therapy. To clarify the mechanisms of the tumor-preferential accumulation of protoporphyrin, we examined the effect of the expression of heme-biosynthetic and -degradative enzymes on the ALA-induced accumulation of protoporphyrin as well as photodamage. The transient expression of heme-biosynthetic enzymes in HeLa cells caused variations of the ALA-induced accumulation of protoporphyrin. When ALA-treated cells were exposed to white light, the extent of photodamage of the cells was dependent on the accumulation of protoporphyrin. The decrease of the accumulation of protoporphyrin was observed in the cells treated with inducers of heme oxygenase (HO)-1. The ALA-dependent accumulation of protoporphyrin was decreased in HeLa cells by transfection with HO-1 and HO-2 cDNA. Conversely, knockdown of HO-1/-2 with siRNAs enhanced the ALA-induced protoporphyrin accumulation and photodamage. The ALA effect was decreased with HeLa cells expressing mitoferrin-2, a mitochondrial iron transporter, whereas it was enhanced by the mitoferrin-2 siRNA transfection. These results indicated that not only the production of porphyrin intermediates but also the reuse of iron from heme and mitochondrial iron utilization control the ALA-induced accumulation of protoporphyrin in cancerous cells.
authors.affiliation: Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ohgari
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Miyata
authors.forename: Taeko
authors.initials: T
authors.lastname: Miyagi
authors.forename: Saki
authors.initials: S
authors.lastname: Gotoh
authors.forename: Takano
authors.initials: T
authors.lastname: Ohta
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Furuyama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Taketani
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism* / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006367:HeLa Cells; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008027:Light; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism* / Q000494:pharmacology; D010957:Plasmids; D011524:Protoporphyrins / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D027682:Cation Transport Proteins; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D034741:RNA, Small Interfering; C425684:SLC25A28 protein, human; D006418:Heme; D000622:Aminolevulinic Acid; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2