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Authors Bu W, Wang Z, Meng L, Li X, Liu X, Chen Y, Xin Y, Li B, Sun H
Received 30 December 2018
Accepted for publication 7 April 2019
Published 1 May 2019 Volume 2019:11 Pages 3887—3898
DOI https://doi.org/10.2147/CMAR.S199912
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 3
Editor who approved publication: Professor Nakshatri
Purpose: Smad4
loss is highly related to poor prognosis and decreased patient survival in oral
squamous cell carcinoma (OSCC), suggesting that agents that target both
Smad4-mutated and Smad4 wild-type cells could treat OSCC more effectively.
Disulfiram (Dsf) has anticancer activity through a variety of mechanisms,
including inhibition of epithelial–mesenchymal transition (EMT). It remains
unclear whether Dsf has the same effect on Smad4-mutated and Smad4 wild-type
OSCC or not and what mechanism is involved.
Methods: Effect of
Dsf on TGFβ1-induced EMT in CAL27 (Smad4 mutation) and
SCC25 (Smad4 wild-type) cells were evaluated through analyzing changes in
morphology, expression of EMT markers, and migration and invasion of cells. The
ERK-pathway inhibitor U0126 was used to confirm TGFβ–ERK–Snail pathway–mediated
cell behavior. Dsf’s effects on tumor growth and metastasis in vivo were
examined through a subcutaneous xenograft mouse model and an intravenous tumor
mouse model.
Results: Dsf
inhibited TGFβ1-induced EMT through suppression of
morphological change, EMT-marker expression, and cell migration and invasion in
both CAL27 and SCC25. Phosphorylation of ERK and expression of Snail were
blocked by Dsf treatment. Like Dsf, U0126 had a similar effect on EMT of CAL27
and SCC25. Dsf also reduced tumor growth and metastasis in vivo, accompanied by
decreased expression of EMT markers in tumors.
Conclusion: These
results indicated that Dsf inhibited EMT of OSCC in vitro and in vivo
independently of Smad4 through suppression of the TGFβ–ERK–Snail pathway,
suggesting the broad-spectrum anticancer potential of Dsf for clinical use
against OSCC.
Keywords: disulfiram,
epithelial–mesenchymal transition, Smad4 mutation, oral squamous cell carcinoma