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Authors Zhou Y, Wang K, Zhou N, Huang T, Zhu J, Li J
Received 17 December 2017
Accepted for publication 9 February 2018
Published 6 April 2018 Volume 2018:11 Pages 2007—2015
DOI https://doi.org/10.2147/OTT.S160119
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 2
Editor who approved publication: Dr Yao Dai
Introduction: In this study, we aimed to investigate the effect of butein on p53 in
hepatocellular carcinoma (HCC) cells and the related molecular mechanisms by
which p53 was activated.
Methods: MTS assay and clonogenic survival assay were used to examine the
antitumor activity of butein in vitro. Reporter gene assay was adopted to
evaluate p53 transcriptional activity. Flow cytometry and western blotting were
performed to study apoptosis induction and protein expression respectively.
Xenograft model was applied to determine the in vivo efficacy and the
expression of p53 in tumor tissue was detected by immunohistochemistry.
Results: HCC cell proliferation and clonogenic survival were significantly
inhibited after butein treatment. With the activation of cleaved-PARP and
capsase-3, butein induced apoptosis in HCC cells in a dose-dependent manner.
The transcriptional activity of p53 was substantially promoted by butein, and
the expression of p53-targeted gene was increased accordingly. Mechanism
studies demonstrated that the interaction between MDM2 and p53 was blocked by
butein and MDM2-mediated p53 ubiquitination was substantially decreased.
Short-hairpin RNA experiment results showed that the sensitivity of HCC cells
to butein was substantially impaired after p53 was knocked down and
butein-induced apoptosis was dramatically decreased. In vivo experiments
validated substantial antitumor efficacy of butein against HepG2 xenograft
growth, and the expression of p53 in butein-treated tumor tissue was
significantly increased.
Conclusion: Butein demonstrated potent antitumor activities in HCC by
activating p53, and butein or its analogs had therapeutic potential for HCC
management.
Keywords: butein, cell apoptosis, hepatocellular carcinoma, MDM2, natural
product, p53, ubiquitination