title: Reactive oxygen species induced by non-steroidal anti-inflammatory drugs enhance the effects of photodynamic therapy in gastric cancer cells.
abstract: Photodynamic therapy is useful for the treatment of cancer because it is minimally invasive for patients. Certain porphyrin compounds and their derivatives have been used as the photosensitizer because they accumulate specifically in cancerous tissues. However, the detailed mechanism of this phenomenon has not been clarified. We previously reported that a proton-coupled folate transporter, HCP1, transported porphyrins and that regulation of the protein was associated with cancer-specific reactive oxygen species from mitochondria (mitROS). Therefore, over-generation of mitROS could increase HCP1 expression and the effect of photodynamic therapy. We investigated whether pretreatment with indomethacin influenced photodynamic therapy by using a rat normal gastric mucosal cell line, RGM1, its cancer-like mutated cell line, RGK1, and a manganese superoxide dismutase (MnSOD)-overexpressing RGK cell line, RGK-MnSOD. Indomethacin promotes the generation of cellular mitROS by inhibiting the electron transport chain, and MnSOD scavenges the mitROS. We elucidated that indomethacin enhanced cancer-specific mitROS generation and increased HCP1 expression. Furthermore, RGK1 cells showed higher cellular incorporation of hematoporphyrin and better therapeutic effect with indomethacin treatment whereas RGK-MnSOD cells did not show a difference. Thus, we concluded that indomethacin improved the effect of photodynamic therapy by inducing increased mitROS generation in cancer cells.
authors.affiliation: Faculty of Medicine, University of Tsukuba, 1-1-1 Tennohdai, Tsukuba 305-8575, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Faculty of Medicine, University of Tsukuba, 1-1-1 Tennohdai, Tsukuba 305-8575, Japan; Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Center for Integrative Medicine, Tsukuba University of Technology, 4-12-7 Kasuga, Tsukuba 305-8521, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Hirayama
authors.affiliation: Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Hiroko P
authors.initials: HP
authors.lastname: Indo
authors.affiliation: Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Hideyuki J
authors.initials: HJ
authors.lastname: Majima
authors.affiliation: Faculty of Medicine, University of Tsukuba, 1-1-1 Tennohdai, Tsukuba 305-8575, Japan.
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
keywords: HCP1; PDT; gastric epithelial cell; indomethacin; mitROS