title: Photodynamic therapy involves an antiangiogenic mechanism and is enhanced by ferrochelatase inhibitor in urothelial carcinoma.
abstract: The purpose of the present study was to investigate the mechanism of photodynamic therapy (PDT) supplemented with exogenously added 5-aminolevulinic acid (ALA) on human urothelial cancer (UC). Moreover, we aimed to determine whether the therapeutic effects of ALA-based PDT (ALA-PDT) for UC could be enhanced by deferoxamine (DFX), an inhibitor of ferrochelatase. The efficiency of ALA-PDT on these cells was analyzed using flow cytometry and the type of cell death was also assessed. The ALA-PDT promoting effect of DFX was examined on both UC cells and human umbilical vein endothelial cells (HUVEC). The ALA-PDT decreased levels of mitochondrial membrane potential and induced cell death mainly via apoptosis in these cells. Moreover, inhibition of ferrochelatase by DFX led to an increase of protoporphyrin IX (PpIX) accumulation and enhanced the effect of ALA-PDT on UC cells. We further investigated the effect of DFX on in vivo PDT with a tumor-bearing animal model and found that DFX efficiently enhanced tumor cell apoptosis. ALA-PDT induced death of neovascular endothelial cells in tumors but did not affect small vessel endothelial cells in normal tissues surrounding the tumor. Furthermore, DFX enhanced inhibition of neovascularization. These results demonstrated ALA-PDT dominantly induced apoptosis over necrosis by direct action on UC as well as via antiangiogenic action on neovacular endothelial cells, suggesting that the therapeutic damage by ALA-PDT could be kept to a minimum in the surrounding normal tissues. In addition, increased accumulation of PpIX by DFX could enhance this effectiveness of ALA-PDT.
authors.affiliation: Department of Urology, Kochi Medical School, Kochi, Japan. keiji@kochi-u.ac.jp
authors.forename: Keiji
authors.initials: K
authors.lastname: Inoue
authors.forename: Hideo
authors.initials: H
authors.lastname: Fukuhara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurabayashi
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagakawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Kozo
authors.initials: K
authors.lastname: Utsumi
authors.forename: Taro
authors.initials: T
authors.lastname: Shuin
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000201:enzymology; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005294:Ferrochelatase / Q000037:antagonists & inhibitors; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011524:Protoporphyrins; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D005294:Ferrochelatase; D003676:Deferoxamine