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

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.

Dihydroartemisinin, an antimalarial drug, induces absent in melanoma 2 inflammasome activation and autophagy in human hepatocellular carcinoma HepG2215 cells

“…Our previous study found that DHA is selective cytotoxicity for some cancer cell lines, such as head and neck squamous cell carcinoma Cal‐27 and Fadu cells (Shi et al, ; Shi, Wang, et al, ). To test the antiproliferative effect of DHA on human HCC cells in vitro, HepG2215 cells were exposed to DHA (5, 10, 20, and 40 μM) for 12, 24, and 36 hr, respectively.…”

“…Accumulating evidence suggests that DHA has numerous mechanisms in cancer cell cytotoxicity and autophagy (Guo, ; Shi, Wang, et al, ). Consistent with these studies, the present research provides a novel description for DHA promotion of autophagy via AIM2/caspase‐1 inflammasome (Figure ).…”

“…Moreover, DHA has anti‐inflammation effects through inhibition Toll‐like receptors (TLR4 and TLR9; Ho, Peh, Chan, & Wong, ). In the previous study, we have demonstrated that DHA promotes autophagy and might be an effective anticancer chemotherapeutic drug on head and neck squamous cell carcinoma (Jia et al, ; Shi et al, ). However, whether or not DHA induces HCC cell death via autophagy or pyroptosis remains unknown.…”

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

“…The mechanism for this first involves the induction of DNA double‐stranded breaks by DHA while it simultaneously increases the number of γH2AX foci. Consequently, the resultant oxidative stress inhibits the nuclear localization of phosphorylated STAT3 and causes autophagic cell death . The inhibitory effect of DHA on STAT3 is also observed in head and neck squamous cell carcinoma, in which DHA serves as a putative STAT3 inhibitor and blocks JAK2 phosphorylation to induce apoptosis .…”

“…Shi et al reported that DHA increases Beclin1 expression in human tongue squamous cell carcinoma, thereby promoting autophagosome formation and eventually causing autophagic cell death. The mechanism for this first involves the induction of DNA double‐stranded breaks by DHA while it simultaneously increases the number of γH2AX foci.…”