Research Papers:

Dihydroartemisinin induces autophagy-dependent death in human tongue squamous cell carcinoma cells through DNA double-strand break-mediated oxidative stress

Xinli Shi, Li Wang, Xiaoming Li _, Jing Bai, Jianchun Li, Shenghao Li, Zeming Wang and Mingrui Zhou

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Oncotarget. 2017; 8:45981-45993. https://doi.org/10.18632/oncotarget.17520

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Xinli Shi1,2,*, Li Wang3,*, Xiaoming Li1, Jing Bai1, Jianchun Li3, Shenghao Li2, Zeming Wang2 and Mingrui Zhou2

1Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang 050081, China

2Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang 050200, China

3Laboratory of Organ Fibrosis Prophylaxis and Treatment by Combine Traditional Chinese and Western Medicine, Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China

*These authors have contributed equally to this work

Correspondence to:

Xiaoming Li, email: [email protected]

Keywords: dihydroartemisinin, human tongue squamous cell carcinoma, autophagy, DNA double-strand break, STAT3

Received: December 16, 2016     Accepted: April 04, 2017     Published: April 29, 2017


Dihydroartemisinin is an effective antimalarial agent with multiple biological activities. In the present investigation, we elucidated its therapeutic potential and working mechanism on human tongue squamous cell carcinoma (TSCC). It was demonstrated that dihydroartemisinin could significantly inhibit cell growth in a dose- and time-dependent manner by the Cell Counting Kit-8 and colony formation assay in vitro. Meanwhile, autophagy was promoted in the Cal-27 cells treated by dihydroartemisinin, evidenced by increased LC3B-II level, increased autophagosome formation, and increased Beclin-1 level compared to dihydroartemisinin-untreated cells. Importantly, dihydroartemisinin caused DNA double-strand break with simultaneously increased γH2AX foci and oxidative stress; this inhibited the nuclear localization of phosphorylated signal transducer and activator of transcription 3 (p-STAT3), finally leading to autophagic cell death. Furthermore, the antitumor effect of dihydroartemisinin-monotherapy was confirmed with a mouse xenograft model, and no kidney injury associated with toxic effect was observed after intraperitoneal injection with dihydroartemisinin for 3 weeks in vivo. In the present study, it was revealed that dihydroartemisinin-induced DNA double-strand break promoted oxidative stress, which decreased p-STAT3 (Tyr705) nuclear localization, and successively increased autophagic cell death in the Cal-27 cells. Thus, dihydroartemisinin alone may represent an effective and safe therapeutic agent for human TSCC.

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