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Sanguinarine exhibits potent efficacy against cervical cancer cells through inhibiting the STAT3 pathway in vitro and in vivo

Authors Zhang H, Zhang J, Venkat PS, Gu C, Meng Y

Received 18 April 2019

Accepted for publication 23 July 2019

Published 14 August 2019 Volume 2019:11 Pages 7557—7566

DOI https://doi.org/10.2147/CMAR.S212744

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Ahmet Emre Eskazan


Huijuan Zhang,*,1 Jing Zhang,*,2 Puja S Venkat,3 Chenglei Gu,1 Yuanguang Meng1

1Department of Gynecology and Obstetrics, The First Medical Center, The General Hospital of the People’s Liberation Army, Beijing, People’s Republic of China; 2Department of Gynecology, Guangdong Hydropower Hospital, Guangdong, People’s Republic of China; 3Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

*These authors contributed equally to this work

Background: Cervical cancer is the third most common malignancy among female cancer patients worldwide. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which regulates a variety of cancer cellular physiological activities including cervical cancer. Sanguinarine (SNG) is a natural plant-derived benzophenanthridine alkaloid that possesses antitumor activities in several cancer cells. However, its anticancer effect on human cervical cancer cells and the underlying mechanisms have not been fully defined.
Methods: In this study, the inhibitory effect of SNG on the proliferation and growth of HeLa cell was detected by MTT assay. Next, cell cycle and apoptosis of HeLa cells was analyzed using Annexin-V/PI double staining and flow cytometry. Then, we measured intracellular ROS generation induced by SNG in HeLa cells by DCFH-DA (10 μM) staining, and the expression level of p-STAT3 and STAT3 was detected by Western blot. Finally, in order to study the effect of SNG on tumor growth in vivo, athymic nude mice were used in the vivo experiments.
Result: This study showed that SNG dose-dependently decreased the tumor cell proliferation and induced a marked increase in cell apoptosis in HeLa cells. Western blot analysis results revealed that SNG-induced antitumor effect might be mediated by STAT3 inhibition. SNG increased the expression of the proapoptotic protein Bax and reduced the expression of the antiapoptotic protein Bcl-2. We further found that SNG dose-dependently increased ROS level in Hela cells. Moreover, pretreatment with N-acetyl-l-cysteine, a scavenger of ROS, almost reversed the SNG-induced anticancer effect. In addition, SNG inhibited human cervical cancer xenograft growth without exhibiting toxicity in vivo.
Conclusion: Our findings highlight STAT3 as a promising therapeutic target. We also demonstrate that SNG is a novel anticancer drug for the treatment of cervical cancer.

Keywords: sanguinarine, STAT3, ROS, apoptosis, cervical cancer


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