Abstract
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.
Highlights
As the number one killer and the most common epithelial cancer identified in the oral cavity, tongue squamous cell carcinoma (TSCC) has the major characteristics of high lymph node metastasis, regional recurrence rate and resultant dissatisfactory treatment outcome [1]
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-Signal transducers and activators of transcription 3 (STAT3)), leading to autophagic cell death
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
Summary
As the number one killer and the most common epithelial cancer identified in the oral cavity, tongue squamous cell carcinoma (TSCC) has the major characteristics of high lymph node metastasis, regional recurrence rate and resultant dissatisfactory treatment outcome [1]. The poor prognosis of the disease and the major side effects of the available pharmacological treatments create an urgent need for de novo chemotherapeutic strategies and drugs. As the active ingredient of Artemisia annua L., Artemisinin has been developed as anti-malarial drug and used worldwide [2]. Dihydroartimisinin (DHA), an FDA-approved artemisinin-derived antimalarial drug, significantly inhibits cancer cell growth www.impactjournals.com/oncotarget in vitro and in vivo [3]. Artemisinin-type drugs are at the stairways to the clinics. There are only limited experimental studies examining the potential of DHA for treating TSCC
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