title: Activation of microbubbles by low-level therapeutic ultrasound enhances the antitumor effects of doxorubicin.
abstract: OBJECTIVE
  To prove that DNA damage, intracellular reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP) are contributing factors for the inhibition of cell proliferation induced by doxorubicin (DOX) administration combined with microbubble-assisted low-level therapeutic ultrasound (US) in K562 cells.
  
  
  METHODS
  3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay was adopted to examine cytotoxicity of different treatments. Changes on apoptosis and necrosis rates, DNA fragmentation, intracellular reactive oxygen species production, mitochondrial membrane potential, cellular membrane permeability and DOX-uptake were analysed by flow cytometry. Nuclear morphology changes were observed under a fluorescence microscope. Ultrasonic cavitation was measured by spectrofluorimetry.
  
  
  RESULTS
  Under optimal conditions, MB-US significantly aggravated DOX-induced K562 cell death, especially necrosis, when compared with either monotherapy. Synergistic potentiation on DNA damage, ROS generation and MMP loss were observed. Ultrasonic cavitation effects, plasma membrane permeabilization and DOX-uptake were notably improved after MB-US exposure.
  
  
  CONCLUSIONS
  MB-US could increase the susceptibility of tumours to antineoplastic drugs, suggesting a potential clinical method for US-mediated tumour chemotherapy.
  
  
  CONCLUSIONS
  • Microbubble-ultrasound (MB-US) aggravated doxorubicin (DOX) induced K562 cell death, especially necrosis • MB-US synergistically potentiated DOX-initiated DNA damage, ROS generation and MMP loss • Ultrasonic cavitation effects, plasma membrane permeabilization and DOX-uptake were improved after treatment • MB-US holds significant potential for improving the efficacy of conventional chemotherapy.
authors.affiliation: Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, Shaanxi, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Su
authors.forename: Quanhong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D003287:Contrast Media; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053078:Membrane Potential, Mitochondrial; D045423:Microbubbles; D017382:Reactive Oxygen Species / Q000378:metabolism; D014464:Ultrasonic Therapy / Q000379:methods*
chemical_list: D000903:Antibiotics, Antineoplastic; D003287:Contrast Media; D017382:Reactive Oxygen Species; D004317:Doxorubicin
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