title: DNA double-strand breaks induced by cavitational mechanical effects of ultrasound in cancer cell lines.
abstract: Ultrasonic technologies pervade the medical field: as a long established imaging modality in clinical diagnostics; and, with the emergence of targeted high intensity focused ultrasound, as a means of thermally ablating tumours. In parallel, the potential of [non-thermal] intermediate intensity ultrasound as a minimally invasive therapy is also being rigorously assessed. Here, induction of apoptosis in cancer cells has been observed, although definitive identification of the underlying mechanism has thus far remained elusive. A likely candidate process has been suggested to involve sonochemical activity, where reactive oxygen species (ROS) mediate the generation of DNA single-strand breaks. Here however, we provide compelling new evidence that strongly supports a purely mechanical mechanism. Moreover, by a combination of specific assays (neutral comet tail and staining for γH2AX foci formation) we demonstrate for the first time that US exposure at even moderate intensities exhibits genotoxic potential, through its facility to generate DNA damage across multiple cancer lines. Notably, colocalization assays highlight that ionizing radiation and ultrasound have distinctly different signatures to their respective γH2AX foci formation patterns, likely reflecting the different stress distributions that initiated damage formation. Furthermore, parallel immuno-blotting suggests that DNA-PKcs have a preferential role in the repair of ultrasound-induced damage.
authors.affiliation: Department of Radiological Sciences, University of Toyama, Toyama, Japan. kondot@med.u-toyama.ac.jp
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Yoshisada
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Paul
authors.initials: P
authors.lastname: Campbell
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Zhao
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ogawa
authors.forename: Mariame Ali
authors.initials: MA
authors.lastname: Hassan
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tabuchi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takasaki
authors.forename: Akihisa
authors.initials: A
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D055595:Mechanical Phenomena; D009025:Morpholines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014465:Ultrasonics
chemical_list: C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D002867:Chromones; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; D011753:Pyrones; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C