title: Mitochondrion-targeted photosensitizer enhances the photodynamic effect-induced mitochondrial dysfunction and apoptosis.
abstract: Recently, the mitochondrion has been considered as a novel pharmacological target for anticancer therapy due to its crucial role involved in arbitrating cell apoptosis. We have previously demonstrated that 488-nm laser irradiation induced a specific mitochondrial reactive oxygen species (mROS) formation and apoptotic death. In this study, we used a second generation of photosensitizers, the benzoporphyrin-derivative monoacid ring A (BPD-MA). We investigated specifically mechanisms at the mitochondrial level for BPD-MA coupled with 690-nm laser irradiation, the photodynamic effect (PDE) of BPD-MA, using conventional and laser scanning imaging microscopy in intact C6 glioma cells. We demonstrated BPD-MA localized mainly in the mitochondrial area. The phototoxicity induced by 1-10 J 690-nm laser irradiation was minor as compared to that induced by 488-nm laser irradiation. Unlike other mitochondrion-targeted photosensitizers, the dark toxicity induced by BPD-MA (0.05-5 mg/mL, effective doses used for the PDE) was relatively low. Nevertheless, the PDE of BPD-MA using 0.5 mg/mL coupled with 5J 690-nm irradiation induced profound and rapid (< 1 min) mitochondrial swelling, mROS formation, and severe plasma membrane blebbing as compared to that induced by 488-nm laser irradiation (< 10 min). Later, the PDE of BPD-MA resulted in positive propidium iodide cell-death stain and positive TUNEL apoptotic nuclear stain and DNA laddering. Finally, the PDT of BPD-MA also instantaneously promoted the mitochondrion to diminish its covalent binding with a mitochondrial marker, MitoTracker Green. We conclude that the PDT of BPD-MA targeted primarily and compellingly the mitochondrion to induce effective mitochondria-mediated apoptosis and thus may serve as a powerful photosensitizer for clinical cancer therapy.
authors.affiliation: Department of Neurology, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Peng
authors.forename: Cheng-Jen
authors.initials: CJ
authors.lastname: Chang
authors.forename: Mei-Jin
authors.initials: MJ
authors.lastname: Guo
authors.forename: Yu-Huai
authors.initials: YH
authors.lastname: Wang
authors.forename: Jau-Song
authors.initials: JS
authors.lastname: Yu
authors.forename: Hong-Yueh
authors.initials: HY
authors.lastname: Wu
authors.forename: Mei-Jie
authors.initials: MJ
authors.lastname: Jou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D008928:Mitochondria / Q000187:drug effects* / Q000528:radiation effects*; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000528:radiation effects; D017319:Photosensitizing Agents / Q000633:toxicity*; D011166:Porphyrins / Q000633:toxicity*; D051381:Rats; D013997:Time Factors; D000077362:Verteporfin
chemical_list: D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin