DNA Double-Strand Breaks Induced by Cavitational Mechanical Effects of Ultrasound in Cancer Cell Lines

Furusawa, Yukihiro; Fujiwara, Yoshisada; Campbell, Paul A.; Zhao, Qing; Ogawa, Ryohei; Hassan, Mona M.; Tabuchi, Yoshiaki; Takasaki, Ichiro; Takahashi, Akihisa; Kondo, Takashi

doi:10.1371/journal.pone.0029012

Cited by 82 publications

(50 citation statements)

References 32 publications

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“…Additionally, cells receiving apoptotic signaling showed H2AX phosphorylation that is DNA-PK dependent [18], which was further corroborated in experiments using DNA-PK inhibitor and TNF-related apoptosis-inducing ligand (TRAIL) [18]. In line with previous research, we reported a reduction in the IRinduced γH2AX positive cell population in cells with an ATM specific inhibitor (KU55933) [12]. In the absence of ATM inhibitor, DNA-PK specific inhibitor (NU7026) did not affected the population of γH2AX positive cell, indicating that ATM is predominant kinase involved in H2AX phosphorylation after IR-exposure.…”

Section: Phosphorylation Of Histone H2ax In Cells Exposed To Ussupporting

confidence: 87%

“…DNA-PK binds to the Ku70/Ku80 heterodimer that binds to and protects DNA ends from degradation, and contributes to DNA repair, such as nonhomologous end joining [27]. In addition to γH2AX foci formation, nuclear localization of phospho-ATM at Ser1981, phospho-DNA-PK at Ser2056/T2609 and phosphor-NBS1 at Ser343, which are activated forms of these proteins [28], were observed in US-treated cells [12]. Immunofluorescence analysis of γH2AX in U937, Jurkat, Molt-4, and HL-60 cells with US, IR (3 Gy), or TRAIL (0.1 mg/mL).…”

Section: Dna Repair Of Us Induced Dsbsmentioning

confidence: 99%

“…This is probably due to the use of classical and relatively insensitive methods for DSB detection (e.g., neutral elution assays and pulse field gel electrophoresis) because these methods require a 50-100 Gy radiation dose to clearly detect the presence of DSBs in the cell nucleus. In recent years, we were the first to detect US-induced DSBs in the cell nucleus by using a highly sensitive method for DSB detection [12]. In human leukemia cells exposed to US, we detected phosphorylation of histone H2AX on Ser139 (γH2AX), a sensitive biomarker for DSBs (detailed in the following section).…”

Section: Us-induced Dna Damagementioning

confidence: 99%

“…Immunofluorescence analysis of γH2AX in U937, Jurkat, Molt-4, and HL-60 cells with US, IR (3 Gy), or TRAIL (0.1 mg/mL). γH2AX staining was performed as described in [12]. Plot profiles of γH2AX intensity in Molt-4 cells were obtained by using NIH Image J software.…”

Section: Dna Repair Of Us Induced Dsbsmentioning

confidence: 99%

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DNA Damage Induced by Ultrasound and Cellular Responses

Furusawa¹,

Kondo²

2017

Mol Biol

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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 tumors. Ultrasound (US) causes multiple thermal and non-thermal effects, such as mechanical and chemical stresses, that can result in damage to the cellular membrane and nucleus, leading to transient membrane pores, alterations in gene expression, and cell death, including apoptosis. On the basis of its biological effects US has been proposed as a new drug delivery and molecular targeting tool for cancer therapy. However, the molecular mechanisms involved in USinduced cell killing are not yet fully understood. Recently, we have reported that the mechanical effects of US elicit DNA single strand as well as double strand breaking-the most cytotoxic form of DNA damage, which initiates subsequent DNA damage response associated with DNA repair, cell cycle arrest, and cell death. Here in the present study we have focused on one of the most significant biological effects of US, i.e., DNA damage and discussed the underlying mechanisms and a unique cellular response. In addition, we have described the characteristic DNA damage response induced by heat stress, which could have caused by the thermal effects of US. Moreover, the study will enrich the literature relevant to furthering our understanding of US for future applications in cancer therapy.

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Section: Phosphorylation Of Histone H2ax In Cells Exposed To Ussupporting

confidence: 87%

Section: Dna Repair Of Us Induced Dsbsmentioning

confidence: 99%

Section: Us-induced Dna Damagementioning

confidence: 99%

Section: Dna Repair Of Us Induced Dsbsmentioning

confidence: 99%

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DNA Damage Induced by Ultrasound and Cellular Responses

Furusawa¹,

Kondo²

2017

Mol Biol

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“…Furusawa et al 103 found that Akt, a substrate of ataxia telangiectasia-mutated and DNA-dependent protein kinase (ATM/DNA-PK), was phosphorylated to the active form in U937 and Molt-4 cell lines without p53 when exposed to ultrasound. Furusawa et al 104 observed induction of apoptosis in cancer cells, which strongly supports involvement of a purely mechanical mechanism. These researchers were the first to demonstrate that exposure to ultrasound at even a moderate level of intensity has genotoxic potential because of its ability to damage DNA in cancer cell lines.…”

Section: Problemsmentioning

confidence: 81%

Potential and problems in ultrasound-responsive drug delivery systems

Zhao¹,

Du²,

Lu³

et al. 2013

IJN

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Abstract:Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS) have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington's disease, thrombolysis, and disruption of the blood-brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future.

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Double‐Strand Breaks in Genome‐Sized DNA Caused by Ultrasound

et al. 2017

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DNA double‐strand breaks (DSBs) caused by ultrasound were evaluated in a quantitative manner by single‐molecule fluorescence microscopy. We compared the effect of time‐interval (or pulse) sonication to that of continuous wave (CW) sonication at a fixed frequency of 30 kHz. Pulses caused fewer DSBs than CW sonication under the same total input ultrasound energy when the pulse repetition period was above the order of a second. In contrast, pulses caused more DSBs than CW sonication for pulse widths shorter than a second. These effect of ultrasound on DNA were interpreted in terms of the time‐dependent decay in the probability of breakage during the duration of a pulse. We propose a simple phenomenological model by considering a characteristic decay in the probability of DSBs during single‐pulse sonication, which reproduces the essence of the experimental trend. In addition, a data analysis revealed a characteristic scaling behavior between the number of pulses and the number of DSBs.

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DNA Double-Strand Breaks Induced by Cavitational Mechanical Effects of Ultrasound in Cancer Cell Lines

Cited by 82 publications

References 32 publications

DNA Damage Induced by Ultrasound and Cellular Responses

DNA Damage Induced by Ultrasound and Cellular Responses

Potential and problems in ultrasound-responsive drug delivery systems

Double‐Strand Breaks in Genome‐Sized DNA Caused by Ultrasound

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