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

Thongchot, Suyanee; Vidoni, Chiara; Ferraresi, Alessandra; Loilome, Watcharin; Yongvanit, Puangrat; Namwat, Nisana; Isidoro, Ciro

doi:10.1002/mc.22893

Cited by 51 publications

(48 citation statements)

References 54 publications

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“…Importantly, its cytotoxic effects were cancer-cell-specific, since only slight toxicity was observed on immortalized cholangiocytes. Beclin1 activation is crucial for dihydroartemisinin action since its genetic depletion or its pharmacologically-mediated degradation inhibits autophagy activation and partially protects CCA cells from dihydroartemisinin treatment [154]. Another drug that promotes Beclin1 activation is pristimerin, which inhibited CCA cell growth in vitro and in vivo, decreasing apoptosis-related proteins Bcl-2, Bcl-XL and procaspase-3, similar to the effect of BH3 mimetics, suggesting pristimerin promotes Beclin1 activation and initiation of autophagy.…”

Section: Autophagy Activatorsmentioning

confidence: 98%

“…Four natural compounds have been recently described to induce CCA cell death, implicating the activation of autophagy as a mediator of their cytotoxic effects:piperlongumine (small molecule extracted from Piper longum plant [151]), pterostilbene (an active constituent of blueberries [152]), pristimerin (a triperpenoid isolated from Maytenus heterophylla [153]) and dihydroartemisinin (an active compound found in Artemisia annua [154]). Although it has been proven that autophagy induction is necessary for their mechanism of action, the specific molecular mechanisms governing their autophagy modulation abilities are not fully understood yet.…”

Section: Autophagy Activatorsmentioning

confidence: 99%

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Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Pérez‐Montoyo

2020

Cells

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Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.

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Section: Autophagy Activatorsmentioning

confidence: 98%

Section: Autophagy Activatorsmentioning

confidence: 99%

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Pérez‐Montoyo

2020

Cells

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“…Besides, EGCG-DHA (docosahexaenoic) ester, a lipophilic derivative of EGCG, shows improved anti-oxidative effects compared to EGCG, and suppresses colon carcinogenesis in mice [112,113]. In the last decade, many studies were carried out using EGCG-loaded nanoparticles including FA-NPS-PEG and FA-PEG-NPS (epigallocatechin gallate-β-lactoglobulin nanoparticles), EGCG-SLN (solid lipid nanoparticle), DT-EGCG-nanoethosomes, FCS-EGCG-NPs (chitosan coated nanoparticles), EGCG-dispersed selenium nanoparticles, 198 AuNP-EGCg (gold nanoparticles), EGCG-loaded microspheres (EGCG/MS), and FCMPs (ferritin-chitosan Maillard reaction products) [6,110,[114][115][116][117][118][119][120][121]. These EGCG nanoparticles can improve the targeting ability and efficacy of EGCG, which greatly promote the clinical application and development of EGCG analogs.…”

Section: Epigallocatechin Gallate (Egcg)mentioning

confidence: 99%

“…Similarly, ART induces apoptosis in murine mastocytome P815 cells and hamster kidney adenocarcinoma BSR cells, and inhibits tumor growth in P815 xenograft mice [177]. Moreover, autophagy plays a vital role in ART-mediated anti-cancer activities [190,[197][198][199][200][201]. DHA can induce autophagy-dependent cell death in human cervical cancer HeLa cells, cholangiocarcinoma KKU-452, KKU-023 and KKU-100, and tongue squamous cell carcinoma Cal-27 cells [190,198,199], while ART induces autophagy-mediated cell cycle arrest in human ovarian cancer SKOV3 cells [200].…”

Section: Artemisininsmentioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including antiproliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

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“…Studies indicated that DHA induced autophagy in different types of cancer cells [22,23,28], whether DHA could mediate autophagy in esophageal cancer remains to be clarified. We transfected GFP-LC3 plasmids into Eca109 cells with the help of lipofectamine 2000 reagent, and massive green LC3 puncta could be observed post 48 h in cells treated with DHA compared with DMSO (Fig.…”

Section: Dha Induces Autophagy In Eca109 Cellsmentioning

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

Cited by 51 publications

References 54 publications

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

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

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