Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

Qu, Chengbin; Ma, Jun; Liu, Xiaobai; Xue, Yixue; Zheng, Jian; Liu, Libo; Liu, Jing; Li, Zhen; Zhang, Lei; Liu, Yunhui

doi:10.3389/fncel.2017.00310

Cited by 41 publications

(28 citation statements)

References 49 publications

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“…In parallel, DHA induced the expression of several autophagy‐related genes, including ATG12, BNIP3, and ULK1, and lowered the expression of mTOR, which normally represses autophagy. These data are in agreement with the reported ability of DHA to induce both apoptosis and autophagy in cancer cells. More than that, our study unravels a novel pathway through which DHA elicits its toxic effect.…”

Section: Discussionsupporting

confidence: 93%

“…21 On testing DHA on six CCA cell lines and on immortalized cholangiocytes, we found that DHA elicited toxicity preferentially toward CCA cells. The IC50 for DHA in the CCA cell lines tested was in the range of 53-61 μM, and the final concentration used to induce cell death was 50 μM, that is in the range of the concentration used in similar in vitro and in vivo studies performed in a variety of cancer types 43,44 including cholangiocarcinoma, 45 hepatocarcinoma, 45 pancreatic cancer, 46,47 lung cancer, 48 18,19,51 and autophagy 12,15,52 in cancer cells. More than that, our study unravels a novel pathway through which DHA elicits its toxic effect.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Thongchot

Vidoni

Ferraresi

et al. 2018

Molecular Carcinogenesis

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Cholangiocarcinoma (CCA) is a very aggressive cancer arising from the malignant transformation of cholangiocytes. Intrahepatic CCA is associated with reactive inflammation and intense fibrosis of the hepatobiliary tract. Dihydroartemisinin (DHA), the active compound found in Artemisia annua, has been shown to possess anti-tumor activity in a variety of human cancers, including hepatoma. Here, we tested the ability of DHA to specifically kill CCA cells and have investigated the underlying mechanisms. DHA induced both apoptosis and autophagy-dependent caspase-independent cell death in many CCA cell lines, while being slightly toxic to immortalized cholangiocytes. DHA induced the expression of many apoptosis- and autophagy-related genes in CCA cells. In particular, it greatly induced the expression of DAPK1, and reduced the interaction of BECLIN1 with BCL-2 while promoting its interaction with PI3KC3. Genetic silencing of DAPK1 prevented DHA-induced autophagy. Pharmacologic and genetic inhibition of BECLIN1 function prevented autophagy and cell death induced by DHA in CCA cells. These data unravel a novel pathway of DHA cancer toxicity and open the possibility to introduce DHA in the therapeutic regimen for the treatment of CCA.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Thongchot

Vidoni

Ferraresi

et al. 2018

Molecular Carcinogenesis

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“…γ-TT was shown to concurrently trigger ER stress and autophagy in inducing apoptosis in breast cancer cells. 55,56 Here, we also observed that abrogation of apoptosis by the pancaspase inhibitor Z-VAD-FMK significantly, but not completely, reverted the cytotoxic effect of δ-TT on CRPC cells. 29 In line with these observations, both the ER stress and the autophagy pathways were reported to mediate the anti-cancer activity of several natural compounds.…”

Section: Discussionsupporting

confidence: 54%

δ‐Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells

et al. 2019

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Objectives: Prostate cancer, after the phase of androgen dependence, may progress to the castration-resistant prostate cancer (CRPC) stage, with resistance to standard therapies. Vitamin E-derived tocotrienols (TTs) possess a significant antitumour activity. Here, we evaluated the anti-cancer properties of δ-TT in CRPC cells (PC3 and DU145) and the related mechanisms of action. Materials and methods:MTT, Trypan blue and colony formation assays were used to assess cell viability/cell death/cytotoxicity. Western blot, immunofluorescence and MTT analyses were utilized to investigate apoptosis, ER stress and autophagy.Morphological changes were investigated by light and transmission electron microscopy. Results:We demonstrated that δ-TT exerts a cytotoxic/proapoptotic activity in CRPC cells. We found that in PC3 cells: (a) δ-TT triggers both the endoplasmic reticulum (ER) stress and autophagy pathways; (b) autophagy induction is related to the ER stress, and this ER stress/autophagy axis is involved in the antitumour activity of δ-TT; in autophagy-defective DU145 cells, only the ER stress pathway is involved in the proapoptotic effects of δ-TT; (c) in both CRPC cell lines, δ-TT also induces an intense vacuolation prevented by the ER stress inhibitor salubrinal and the protein synthesis inhibitor cycloheximide, together with increased levels of phosphorylated JNK and p38, supporting the induction of paraptosis by δ-TT.Conclusions: These data demonstrate that apoptosis, involving ER stress and autophagy (in autophagy positive PC3 cells), and paraptosis are involved in the anti-cancer activity of δ-TT in CRPC cells.

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“…It was found that autophagic cell death played an important role in anticancer drugs [20,21]. DHA could induce autophagy in some human cancer cell lines, including esophageal cancer cells [22][23][24], while the precise mechanisms of DHA on cancer cells were still limited. In the present study, we explored the role of autophagy in DHA treated Eca109 cells and the associated mechanisms were identified as well.…”

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confidence: 99%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

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Background: Dihydroartemisinin (DHA), a derivate of artemisinin, is an effective antimalarial agent. DHA has been shown to exert anticancer activities to numerous cancer cells in the past few years, while the exact molecular mechanisms remain to be elucidated, especially in esophageal cancer. Methods: Crystal violet assay was conducted to determine the cell viability of human esophageal cancer cell line Eca109 treated with DHA. Tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Soft agar and crystal violet assays were used to measure the tumorigenicity of Eca109 cells. Flow cytometry was performed to evaluate ROS or cell cycle distribution. GFP-LC3 plasmids were delivered into Eca109 cells to visualize autophagy induced by DHA under a fluorescence microscope. The mRNA and protein levels of each gene were tested by qRT-PCR and western blot, respectively. Results: Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose-and time-dependent manner. Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells. Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells, while blocking ROS by an antioxidant NAC obviously inhibited autophagy. Furthermore, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation, which could be rescued after autophagy was blocked by ROS inhibition. Moreover, the DNA damage response (DDR) was induced obviously in DHA treated cells. To further explore whether ROS or autophagy played a vital role in DHA induced cell cycle arrest, the cell cycle distribution of Eca109 cells was evaluated after ROS or autophagy blocking, and the results showed that autophagy, but not ROS, was essential for cell cycle arrest in DHA treated cells. Conclusion: Taken together, DHA showed anticancer effect on esophageal cancer cells through autophagy-dependent cell cycle arrest at the G2/M phase, which unveiled a novel mechanism of DHA as a chemotherapeutic agent, and the degradation of TRF2 followed by DDR might be responsible for this cell phenotype.

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Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells

Cited by 41 publications

References 49 publications

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

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

δ‐Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

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