Abstract
Dihydroartemisinin (DHA), an active metabolite and derivative of artemisinin, is the most effective antimalarial drug and has strong antitumor activity in various tumor types. It has recently been reported that DHA can induce autophagy and has significant effects on multiple myeloma (MM), but the mechanisms and the relationship between the autophagy and apoptosis induced by DHA remain to be elucidated. Herein, we demonstrated that DHA significantly induces cell death in a dose- and time-dependent manner via the extrinsic and intrinsic apoptosis pathways. Moreover, DHA-induced autophagy, which plays a prodeath role in MM, can regulate canonical apoptosis and vice versa. Furthermore, the P38/MAPK signaling pathway is responsible for decreased autophagy and increased apoptosis. DHA induces autophagy and apoptosis also through the inhibition of the Wnt/β-catenin signaling pathway. In addition, DHA shows a strong effect in a xenograft mouse model. Collectively, these findings reveal that DHA, as an artemisinin-based drug, could be an effective and safe therapeutic agent for MM.
Highlights
Multiple myeloma (MM) is an incurable malignancy disease characterized by clonal plasma cell accumulation in the bone marrow accompanied by the secretion of monoclonal immunoglobulins in the serum and/or urine [1, 2]
To investigate the potential inhibition of cell growth of DHA on MM, the human myeloma cell lines (HMCLs) CAG, JJN3, and RPMI-8226 were treated with increasing concentrations of DHA for h, 48 h, and 72 h, respectively, and cell viability was evaluated by a Cell Counting Kit-8 (CCK-8) assay (Figure 1(a))
We examined the effect of DHA on apoptosis induction by Annexin
Summary
Multiple myeloma (MM) is an incurable malignancy disease characterized by clonal plasma cell accumulation in the bone marrow accompanied by the secretion of monoclonal immunoglobulins in the serum and/or urine [1, 2]. MM cell death with minimal side effects would provide significant clinical benefits. Emerging studies have shown that DHA has strong antitumor activity in various tumor types by inhibiting cell proliferation, arresting the cell cycle, promoting apoptosis, and inhibiting angiogenesis and metastasis [6,7,8,9]. Previous studies have reported that DHA induces autophagy and inhibits MM cell proliferation [10, 11]. It can serve as a cell survival mechanism, and in others, it can lead to cell death, either in collaboration with apoptosis or as a back-up mechanism [13]. Previous studies have shown that DHA induces autophagy in MM cells, whether autophagy actively induces cell death or is a cell response mechanism and the mechanisms underlying the apoptosis and autophagy induced by DHA are still unclear
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