Journal
ULTRASOUND IN MEDICINE AND BIOLOGY
Volume 41, Issue 10, Pages 2755-2764Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ultrasmedbio.2015.05.021
Keywords
Microbubble; Acoustic cavitation; Mitochondrial permeability transition pore; Cytochrome c; Cyclosporin A
Funding
- National Basic Research Program 973 of the Ministry of Science and Technology of China [2011 CB707903]
- National Natural Science Foundation of China [81127901, 81201105]
- Natural Science Basic Research Plan in Shaanxi Province of China [2015JQ8313]
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Acoustic cavitation of microbubbles has been described as inducing tumor cell apoptosis that is partly associated with mitochondrial dysfunction; however, the exact mechanisms have not been fully characterized. Here, low-intensity pulsed ultrasound (1 MHz, 0.3-MPa peak negative pressure, 10% duty cycle and 1-kHz pulse repetition frequency) was applied to K562 chronic myelogenous leukemia cells for 1 min with 10% (v/v) SonoVue microbubbles. After ultrasound exposure, the apoptotic index was determined by flow cytometry with annexin V-fluorescein isothiocyanate/propidium iodide. In addition, mitochondrial membrane potential (Delta psi(m)) was determined with the JC-1 assay. Translocation of apoptosis-associated protein cytochrome c was evaluated byWestern blotting. We found that microbubble-assisted acoustic cavitation can increase the cellular apoptotic index, mitochondrial depolarization and cytochrome c release in K562 cells, compared with ultrasound treatment alone. Furthermore, mitochondrial dysfunction and apoptosis were significantly inhibited by cyclosporin A, a classic inhibitor of the mitochondrial permeability transition pore; however, the inhibitor of Bax protein, Bax-inhibiting peptide, could not suppress these effects. Our results suggest that mitochondrial permeability transition pore opening is involved in mitochondrial dysfunction after exposure to microbubble-assisted acoustic cavitation. Moreover, the release of cytochrome c from the mitochondria is dependent on cyclosporin A-sensitive mitochondrial permeability transition pore opening, but not formation of the Bax-voltage dependent anion channel complex or Bax oligomeric pores. These data provide more insight into the mechanisms underlying mitochondrial dysfunction induced by acoustic cavitation and can be used as a basis for therapy. (E-mail: fengyi@mail.xjtu.edu.cn or mxwan@mail.xjtu.edu.cn) (C) 2015 World Federation for Ultrasound in Medicine & Biology.
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