title: Tailor-made approach to photodynamic therapy in the treatment of cancer based on Bcl-2 photodamage.
abstract: It is very important to elucidate the mechanism of action and identify the molecular determinant of photodynamic medicine, in order to increase the number of clinical applications of photodynamic therapy (PDT) and perform personalized medicine. We have previously reported that PDT using some photosensitizers, such as phthalocyanine 4 (Pc 4) damages the anti-apoptotic protein Bcl-2, and that Bcl-2 is a molecular PDT target using a mitochondrion-targeting photosensitizer. In this study, we examined the molecular targets of Photofrin-PDT and NPe6-PDT, which are approved for early stage lung cancers by the Japanese Ministry of Health Labor and Welfare, by evaluating the photodamage to Bcl-2 using Western blot analysis. Our results showed that Photofrin-PDT damaged Bcl-2, induced morphologically typical apoptosis, and demonstrated equal sensitivity between MCF-7c3 cells (human breast cancer cells expressing stably transfected procaspase-3) and Bcl-2 overexpressing cells, MCF-7c3-GFP-Bcl-2 cells, with a clonogenic assay. However, NPe6-PDT did not damage Bcl-2 and took longer to induce typical apoptosis compared with Photofrin-PDT. MCF-7c3-GFP-Bcl-2 cells were considerably more resistant to the lethal effects of NPe6-PDT than parental MCF-7c3 cells. In conclusion, Photofrin-PDT damages different molecular targets, and our data indicate that the extent of Bcl-2 photodamage can determine the sensitivity of cancer cells to apoptosis and to overall cell killing caused by PDT using Photofrin, but not the lysosomal targeting NPe6. The application of these findings to clinical PDT may depend on the levels of the Bcl-2 proteins in the tumor being treated, and the tailor-made medicine based on the Bcl-2 photodamage may overcome any resistance afforded by elevated amounts of Bcl-2.
authors.affiliation: Department of Thoracic Surgery, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan. jusuda@tokyo-med.ac.jp
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Usuda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirata
authors.forename: Shuji
authors.initials: S
authors.lastname: Ichinose
authors.forename: Taichirou
authors.initials: T
authors.lastname: Ishizumi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.forename: Keishi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Sachio
authors.initials: S
authors.lastname: Maehara
authors.forename: Masae
authors.initials: M
authors.lastname: Yamada
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okunaka
authors.forename: Harubumi
authors.initials: H
authors.lastname: Kato
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ikeda
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D006801:Humans; D007834:Lasers; D008027:Light; D008495:Medical Oncology / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014162:Transfection
chemical_list: D017319:Photosensitizing Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D004247:DNA