Abstract
Background: In this study, we investigated the induction of apoptosis by ultrasound in the presence of the photochemically active chlorine, 4-formyloximeetylidene-3-hydroxyl-2-vinyl-deuterio-porphynyl (IX)-6-7-diaspartic acid (ATX-S10). Methods: HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of ATX-S10, and the induction of apoptosis was examined by analyzing cell morphology, DNA fragmentation, and caspase-3 activity. Results: Cells treated with 80μM ATX-S10 and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas significant morphologic changes were not observed in cells exposed to either ultrasound or ATX-S10 alone. Also, DNA ladder formation and caspase-3 activation were observed in cells treated with both ultrasound and ATX-S10 but not in cells treated with ultrasound or ATX-S10 alone. In addition, the combination of ATX-S10 and the same acoustical arrangement of ultrasound substantially enhanced nitroxide generation by the cells. Sonodynamically induced apoptosis, caspase-3 activation, and nitroxide generation were significantly suppressed by histidine. Conclusions: These results indicate that the combination of ultrasound and ATX-S10 induces apoptosis in HL-60 cells. The significant reduction in sonodynamically induced apoptosis, nitroxide generation, and caspase-3 activation by histidine suggests active species such as singlet oxygen are important in the sonodynamic induction of apoptosis. General significance: The results reported in this paper are experimental, but they significantly support the possibility of sonodynamic treatment for cancer using the induction of apoptosis.
Highlights
Ultrasound has a tissue attenuation coefficient that allows it to penetrate intervening tissues and reach internal targets without losing the ability to focus energy into small volumes
We found that photochemically active porphyrins such as hematoporphyrin, Porfimer Sodium (PF) and a gallium porphyrin complex, 7,12-bis(1-decyloxyethyl)-Ga(III)-3,8,13,17-tetramethylporphyrin 2,18-dipropionyl diaspartic acid (ATX-70) can induce significant cell damage when activated by ultrasound [8,9]
Following exposure to ultrasound for 3 min in the presence and absence of ATX-S10, the fraction of unstained cells was 80% and 56%, respectively
Summary
Ultrasound has a tissue attenuation coefficient that allows it to penetrate intervening tissues and reach internal targets without losing the ability to focus energy into small volumes. This is a unique advantage over electromagnetic modalities such as laser light and microwaves for the noninvasive treatment of internal tumors. We found that photochemically active porphyrins such as hematoporphyrin, Porfimer Sodium (PF) and a gallium porphyrin complex, 7,12-bis(1-decyloxyethyl)-Ga(III)-3,8,13,17-tetramethylporphyrin 2,18-dipropionyl diaspartic acid (ATX-70) can induce significant cell damage when activated by ultrasound [8,9]. Photochemically active porphyrins may be useful for sensitizing tumors to ultrasound. We investigated the induction of apoptosis by ultrasound in the presence of the photochemically active chlorine, 4-formyloximeetylidene-3-hydroxyl-2-vinyl-deuterio-porphynyl (IX)-6-7-diaspartic acid (ATX-S10)
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