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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

Doxorubicin combined with low intensity ultrasound suppresses the growth of oral squamous cell carcinoma in culture and in xenografts

Authors: Haixia Fan, Haixia Li, Guanyao Liu, Wei Cong, Hong Zhao, Wenwu Cao, Jinhua Zheng

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

Oral squamous cell carcinoma (OSCC) invades surrounding tissues by upregulating matrix metalloproteinases (MMPs) -2 and −9, which causes over-expression of the Hedgehog signaling proteins Shh and Gli-1 and degradation of the extracellular matrix, thereby creating a “highway” for tumor invasion. We explored the potential of low intensity ultrasound (LIUS) and doxorubicin (DOX) to inhibit the formation of this “highway”.

Methods

MTT assays were used to examine OSCC cell viability after exposure to LIUS and DOX. The cell morphological changes and ultrastructure were detected by scanning electron microscopy and transmission electron microscopy. Endogenous autophagy-associated proteins were analyzed by immunofluorescent staining and western blotting. Cell migration and invasion abilities were evaluated by Transwell assays. Collagen fiber changes were evaluated by Masson’s trichrome staining. Invasion-associated proteins were analyzed by immunohistochemistry and western blotting.

Results

LIUS of 1 W/cm2 increased the in vitro DOX uptake into OSCC by nearly 3-fold in three different cell lines and induced transient autophagic vacuoles on the cell surface. The combination of LIUS and 0.2 μg/ml DOX inhibited tumor cell viability and invasion, promoted tumor stromal collagen deposition, and prolonged the survival of mice. This combination also down-regulated MMP-2, MMP-9, Shh and Gli-1 in tumor xenografts. Collagen fiber expression was negatively correlated with the expression of these proteins in human OSCC samples.

Conclusions

Our findings suggest that effective low dosages of DOX in combination with LIUS can inhibit cell proliferation, migration and invasion, which might be through MMP-2/9 production mediated by the Hedgehog signaling pathway.
Appendix
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Metadata
Title
Doxorubicin combined with low intensity ultrasound suppresses the growth of oral squamous cell carcinoma in culture and in xenografts
Authors
Haixia Fan
Haixia Li
Guanyao Liu
Wei Cong
Hong Zhao
Wenwu Cao
Jinhua Zheng
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0633-y

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