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 Warburgs 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”.
Keywords: Acridine orange, photodynamic therapy, cancer acidity, lysosome, proton, musculoskeletal sarcomas, Warburg's effect, neutral pH, cytosolic fluid, apoptosis
Current Pharmaceutical Design
Title: Translational Research of Photodynamic Therapy with Acridine Orange which Targets Cancer Acidity
Volume: 18 Issue: 10
Author(s): Katsuyuki Kusuzaki, Shigekuni Hosogi, Eishi Ashihara, Takao Matsubara, Haruhiko Satonaka, Tomoki Nakamura, Akihiko Matsumine, Akihiro Sudo, Atsumasa Uchida, Hiroaki Murata, Nicola Baldini, Stefano Fais and Yoshinori Marunaka
Affiliation:
Keywords: Acridine orange, photodynamic therapy, cancer acidity, lysosome, proton, musculoskeletal sarcomas, Warburg's effect, neutral pH, cytosolic fluid, apoptosis
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 Warburgs 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”.
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Cite this article as:
Kusuzaki Katsuyuki, Hosogi Shigekuni, Ashihara Eishi, Matsubara Takao, Satonaka Haruhiko, Nakamura Tomoki, Matsumine Akihiko, Sudo Akihiro, Uchida Atsumasa, Murata Hiroaki, Baldini Nicola, Fais Stefano and Marunaka Yoshinori, Translational Research of Photodynamic Therapy with Acridine Orange which Targets Cancer Acidity, Current Pharmaceutical Design 2012; 18 (10) . https://dx.doi.org/10.2174/138161212799504812
DOI https://dx.doi.org/10.2174/138161212799504812 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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