Review. Acridine orange could be an innovative anticancer agent under photon energy.
Acridine orange (AO) was extracted as a dye from coal tar over a hundred years ago. It has various unique biological activities and has been shown to be a useful fluorescent dye specific for DNA and RNA, a pH indicator, photosensitizer, antitumor and antimalarial drug, and detector of bacteria and parasites. It has recently been found that AO accumulates in musculoskeletal sarcomas and that after illumination of the tumors with visible light or irradiation with low-dose X-rays, the dye rapidly exerts selective cytocidal effect against the sarcoma cells. Therefore, surgery combined with photo- (PDT) or radiodynamic therapy (RDT) with AO (AO-PDT and -RDT) has been applied to human musculoskeletal sarcomas. The results of a clinical study on the outcome of this therapeutic strategy revealed that it yielded better local control and remarkably better limb function than wide resectional surgery. Based on our experimental studies, it was clarified that AO accumulates in acidic organelles or structures, especially lysosomes, depending on the acidity. An enormous number of protons are produced in cancer from lactate or CO2 under hypoxic conditions, which are moved into the extracellular fluid or lysosomes to maintain the intracellularfluid pH. Therefore, AO shows marked accumulation in the acidic lysosomes of cancer cells. Photon energy from visible light or X-rays excites the AO accumulated in lysosomes; the excited AO emits fluorescence and forms activated oxygen from intra-cytoplasmic oxygen. The activated oxygen destroys lysosomes, with the released lysosomal enzymes causing rapid death of the cancer cells. On the other hand, normal cells can exclude AO quickly because they are not acidic. Thus, AO-PDT and AO-RDT exhibit strong and selective cytocidal effect against malignant tumors. In conclusion, we believe that AO-PDT and AO-RDT exhibit selective anticancer cell activity and that AO excited by photon energy has excellent potential as an anticancer agent.
Kusuzaki
Katsuyuki
K
Department of Cancer Center, Mie University Faculty of Medicine, Tsu, Japan. kusu@clin.medic.mie-u.ac.jp
Murata
Hiroaki
H
Matsubara
Takao
T
Satonaka
Haruhiko
H
Wakabayashi
Toru
T
Matsumine
Akihiko
A
Uchida
Atsumasa
A
D000165:Acridine Orange / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D051642:Histiocytoma / Q000188:drug therapy; D051677:Histiocytoma, Malignant Fibrous / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009140:Musculoskeletal Diseases / Q000188:drug therapy / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D017785:Photons / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D000165:Acridine Orange