Dihydroartemisinin increases temozolomide efficacy in glioma cells by inducing autophagy

Abstract

Abstract. Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb, Artemisia annua L., and has the ability to inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to inhibit the growth of a variety of types of human cancer. However, the effect of DHA on human glioma cells remains unclear. The aim of the present study was to investigate the effect of DHA on the proliferation of glioma cells, and whether DHA was able to enhance temozolomide (TMZ) sensitivity in vitro and in vivo. In total, 10 human glioma cell lines were used to analyze the growth inhibition ability of DHA by MTT assay. The typical autophagic vacuoles were monitored by the application of the autofluorescent agent, monodansylcadaverine. Western blotting was used to detect markers of apoptosis and autophagy, namely Caspase-3, Beclin-1 and LC3-B. The combination efficiency of DHA and TMZ was assessed in vitro and in vivo. The half maximal inhibitory concentration (IC 50 ) of DHA differed among the ten human glioma cell lines. The number of autophagic vacuoles was higher in DHA-treated SKMG-4 cells; this was highest of all cell lines analyzed. The expression of autophagy molecular markers, Beclin-1 and LC3-B, was increased following DHA treatment, while no significant alteration was detected in the expression of apoptotic marker Caspase-3. When combined with DHA, the IC 50 of TMZ decreased significantly in the four glioma cell lines analyzed. Furthermore, DHA enhanced the tumor inhibition ability of TMZ in tumor-burdened mice. The results of the present study demonstrated that DHA inhibited the proliferation of glioma cells and enhanced the tumor inhibition efficacy of TMZ in vitro and in vivo through the induction of autophagy.

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

“…However, ATG5-siRNA-induced autophagic inhibition reversed the expression of DHA-inhibited catabolic genes and chemokines. Consistent with our results, autophagy was also activated by DHA in myeloma cancer and glioma cells2028. In the HeLa and HCT116 cells, DHA induced autophagy by upregulating the level of stress-regulated protein p8, and the activation of autophagy attenuated the DHA-induced apoptosis adaptively29.…”

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

“…In contrast, temozolomideinduced cell death did not implicate caspase-3 activation, suggesting the involvement of other modes of cell death, such as autophagy [72]. Autophagy is usually reduced in cells with a large number of lipid droplets, which could partly explain the limited effectiveness of temozolomide against glioblastoma tumors [73,74].…”

Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

“…8,9 The anti-malarial drug dihydroartemisinin (DHA) has been shown to possess therapeutic effects in several in vitro and in vivo cancer models by activating both caspase-dependent and caspaseindependent death pathways. [10][11][12][13][14][15] Since DHA has been proven to kill hepatomas [16][17][18][19] and to reduce fibrosis in the liver following bile duct ligation, 20 we reasoned that it could be a good candidate chemotherapeutics for CCA. Interestingly, DHA could alleviate liver fibrosis through autophagy-mediated induction of senescence in hepatic stellate stem cells.…”