Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling

Abstract

Non-small-cell lung cancer (NSCLC) is the most prevalent malignancy worldwide given its high incidence, considerable mortality, and poor prognosis. The anti-malaria compounds artemisinin (ART), dihydroartemisinin (DHA), and artesunate (ARTS) reportedly have anti-cancer potential, although the underlying mechanisms remain unclear. In this work, we used flow cytometry to show that ART, DHA, and ARTS could inhibit the proliferation of A549 and H1299 cells by arresting cell cycle in G1 phase. Meanwhile, tumor malignancy including migration, invasion, cancer stem cells, and epithelial–mesenchymal transition were also significantly suppressed by these compounds. Furthermore, ART, DHA, and ARTS remarkably decreased tumor growth in vivo. By using IWP-2, the inhibitor of Wnt/β-catenin pathway, and Wnt5a siRNA, we found that ART, DHA, and ARTS could render tumor inhibition partially dependent on Wnt/β-catenin inactivation. These compounds could strikingly decrease the protein level of Wnt5-a/b and simultaneously increase those of NKD2 and Axin2, ultimately resulting in β-catenin downregulation. In summary, our findings revealed that ART, DHA, and ARTS could suppress lung-tumor progression by inhibiting Wnt/β-catenin pathway, thereby suggesting a novel target for ART, DHA, and ARTS in cancer treatment.

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

“…Tong et al. described a suppressive effect on NSCLC CSCs by artemisinin, as reflected by a reduction in CSC markers such as Sox2 and Oct4 . This was linked to an artemisinin‐mediated inactivation of the Wnt/β‐catenin pathway, which is a well‐documented mechanism of action for artemisinin in the context of cancer.…”

“…Tong et al described a suppressive effect on NSCLC CSCs by artemisinin, as reflected by a reduction in CSC markers such as Sox2 and Oct4. 123 This was linked to an artemisinin-mediated inactivation of the Wnt/ -catenin pathway, which is a well-documented mechanism of action for artemisinin in the context of cancer. Separately, Berte et al investigated the combination of artemisinin and temozolomide (first-line chemotherapy drug for glioblastoma) in glioma and glioma stem like cell lines.…”

Effect of dihydroarteminin combined with siRNA targeting Notch1 on Notch1/c-Myc signaling in T-cell lymphoma cells

“…Additionally, DHA exerts an antineoplastic effect in prostate cancer cells by increasing death receptor 5 expression (24) and induces NOXA-dependent mitochondrial cell apoptosis in melanoma cells with upregulation of cellular oxidative stress (25), furthermore, DHA triggers cell cycle arrest via effects on the AKT/GSK3β/cyclin D1 pathway in A549 lung cancer cells (26). DHA could also inhibit the Wnt/β-catenin signaling pathway in lung cancer, and the expressions of key proteins including Wnt5-a/b, LRP6 and Dvl2 in the Wnt/β-catenin signaling pathway were significantly decreased (27). More importantly, DHA has been shown to increase reactive oxygen species generation, downregulate transferrin receptor mRNA expression and telomerase activity, upregulate NOXA protein in T-cell lymphoma cells (13,28).…”

Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence

“…[6][7][8][9][10] Several other studies have also shown that ARSs promote cell apoptosis and inhibit invasion in glioma, 33 and the mechanisms involve AKT signalling 34 and ROS-β-catenin signalling. 35 However, the roles of ARS compounds in cancer metabolism have never been elucidated. In the present study, we demonstrated that the ARS analogue ART could inhibit glioma malignancy through two mechanisms: (a) inhibiting the nuclear localization of SREBP2 and its target gene HMGCR, which have been demonstrated to be oncogenes, and (b) disrupting the interaction between SREBP2 and P53, which up-regulated P21 expression and induced senescence ( Figure 6).…”