title: Translational research of photodynamic therapy with acridine orange which targets cancer acidity.
abstract: During the past 20 years, we have found that acridine orange (AO) selectively accumulates in musculoskeletal sarcomas in vivo or exerts selective cytocidal effects against sarcoma cells in vitro after illumination of the tumor cells with visible light or irradiation of the cells with low-dose X-rays. Based on the data obtained from basic research, we have employed reduction surgery followed by photo- or radiodynamic therapy using AO (AO-PDT & RDT) in 71 patients with musculoskeletal sarcomas, in an attempt to maintain excellent limb function in the patients. We have obtained good local control rates and remarkably better limb functions with this approach as compared to the results obtained with the conventional wide resection surgery. Our basic research demonstrated that AO accumulates densely in intracellular acidic vesicles, especially lysosomes, in an acidity-dependent manner. In cancer cells that proliferate under hypoxic conditions or with Warburg's effect, active glycolysis produces an enormous number of protons, which are released by the cells via proton pumps into the extracellular fluid or lysosomes to maintain a neutral pH of the cytosolic fluid. Cancer cells contain many strongly acidic lysosomes of large sizes; therefore, AO shows marked and prolonged accumulation in the acidic lysosomes of cancer cells. Photon energy excites the AO resulting in the production of activated oxygen species, which oxidize the fatty acids of the lysosomal membrane, resulting in the leakage of lysosomal enzymes and protons, followed by apoptosis of the cancer cells. Based on these observations, we conclude that AO-PDT & RDT target acidic vesicles, especially the lysosomes, in cancer cells, to exhibit selective anti-cancer cell activity. Therefore, it is suggested that AO excited by photon energy has excellent potential as an anticancer "Magic Bullet".
authors.affiliation: Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi Hirokoji Kajiicho 465, Kamigyo-ku Kyoto 602-8566, Japan. kusuzaki@kpu-m.ac.jp
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kusuzaki
authors.forename: Shigekuni
authors.initials: S
authors.lastname: Hosogi
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.forename: Takao
authors.initials: T
authors.lastname: Matsubara
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Satonaka
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsumine
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sudo
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Uchida
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Murata
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Marunaka
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects*; D000165:Acridine Orange / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D015394:Molecular Structure; D010778:Photochemotherapy; D012509:Sarcoma / Q000188:drug therapy*; D057170:Translational Research, Biomedical
chemical_list: D000165:Acridine Orange