PMID: 

Biochem Pharmacol. 2010 Jan 15 ;79(2):130-6. Epub 2009 Aug 19. PMID: 19698702

Abstract Title: 

Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines.

Abstract: 

Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active. Artesunate-induced apoptosis and reactive oxygen species in neuroblastoma cells. Of 16 cell lines and two primary cultures, only UKF-NB-3(r)CDDP(1000) showed low sensitivity to artesunate. Characteristic gene expression signatures based on a previous analysis of artesunate resistance in the NCI60 cell line panel clearly separated UKF-NB-3(r)CDDP(1000) from the other cell lines. l-Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate-cysteine ligase), resensitised in part UKF-NB-3(r)CDDP(1000) cells to artesunate. This finding together with bioinformatic analysis of expression of genes involved in glutathione metabolism showed that this pathway is involved in artesunate resistance. These data indicate that neuroblastoma represents an artesunate-sensitive cancer entity and that artesunate is also effective in chemoresistant neuroblastoma cells.

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PMID: 

Exp Mol Pathol. 2019 04 ;107:10-22. Epub 2019 Jan 17. PMID: 30660598

Abstract Title: 

The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells.

Abstract: 

Breast cancer is the most prevalent cancer diagnosis in women, with triple-negative and human epidermal growth factor 2 (HER2)-enriched advanced breast cancers having the poorest prognoses. The morbidity and mortality associated with advanced disease, as well as the emergence of multi-drug resistant variants, highlights the urgency to develop novel therapeutic agents. Artesunate (ART) is a semi-synthetic derivative of artemisinin from the Chinese herb sweet wormwood. ART is widely used in the treatment of malaria and is well tolerated by patients. Importantly, ART also has anti-cancer activities and may therefore represent a less toxic alternative to conventional chemotherapy. In this study, we demonstrate a dose- and time-dependent inhibitory effect of ART on the growth of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells, which was the result of both anti-proliferative and cytotoxic activities. ART inhibited breast cancer cell proliferation via a reactive oxygen species (ROS)-dependent G2/M arrest and ROS-independent G1 arrest. ART-treated MDA-MB-468 and SK-BR-3 cells also experienced apoptotic cell death, which was both ROS- and iron-dependent. ART-induced oxidative stress caused the loss of mitochondrial outer membrane integrity and damage to the cellular DNA of MDA-MB-468 and SK-BR-3 cells. In addition, exposure to low-dose ART sensitized MDA-MB-468 and SK-BR-3 cells to chemotherapeutic drugs. On the basis of our findings, we suggest that ART may have clinical utility in the treatment of triple-negative and HER2-enriched breast cancers.

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PMID: 

Eur Rev Med Pharmacol Sci. 2014 ;18(21):3199-204. PMID: 25487928

Abstract Title: 

Artesunate restraining MAPK passage by smad7 to resist pulmonary fibrosis.

Abstract: 

OBJECTIVES: This study aims to discuss the function and molecular mechanism of artesunate in resisting pulmonary fibrosis.METHODS: Artesunate was used to stimulate the HFL-I cell line, which restrains the expression of Smad7 protein. Under different conditions, all treatment factors were checked, including Smad7, p-P38, ERK, and p-JNK protein expressions. Flow cytometry was used to detect the cell cycle. For the silent expression of the p-Smad7 protein, Western blot analysis revealed that Smad7, p-P38, and p-JNK proteins decreased compared with those of the non-treatment group.RESULTS: No significant changes were observed in Smad7, p-P38, and p-JNK proteins after the cells with silent p-Smad7 protein expression were stimulated by artesunate (p>0.5). No significant changes were observed in the expression of Smad7, p-P38, and p-JNK proteins after using TGF-β1 recombination factor to cells whose p-Smad7 protein expression is silent (p>0.5).CONCLUSIONS: Artesunate blocks the MAPK cell conduction pathway through Smad7 to restrain idiopathic pulmonary fibrosis.

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PMID: 

Antivir Ther. 2016 ;21(6):535-539. Epub 2016 Feb 4. PMID: 26844400

Abstract Title: 

Artesunate demonstrates in vitro synergism with several antiviral agents against human cytomegalovirus.

Abstract: 

BACKGROUND: Human cytomegalovirus (HCMV) infections remain a major problem in immunocompromised patients. Three antiviral agents, ganciclovir (GCV), foscarnet (FOS) and cidofovir (CDV), are currently approved for the treatment of HCMV infections. They all target the viral DNA polymerase and are associated with significant side effects. Combinations of novel antiviral compounds acting on different targets such as artesunate (ART) with currently approved drugs or eventually letermovir or maribavir (MBV) may result in synergistic effects. Here, we evaluated the in vitro activity of a series of two-drug combinations against a wild-type recombinant HCMV strain by the Gaussia luciferase (GLuc) reporter assay.METHODS: The in vitro activity of each drug was first tested individually against HCMV by using the GLuc reporter assay. The activity of two-drug combinations consisting of ART and currently approved drugs, as well as letermovir or MBV, was then analysed by the Chou-Talalay method.RESULTS: The concentrations of GCV, FOS, CDV and ART that reduced the GLuc activity by 50% (ECvalues) were 3.92±1.64 µM, 62.45 ±8.39 µM, 0.68 ±0.19 µM and 3.86 ±1.25 µM, respectively, whereas those of MBV and letermovir were 64 ±22 nM and 2.50 ±0.83 nM, respectively. The combination of ART with GCV, CDV or MBV was associated with synergism, whereas combination of ART with FOS or letermovir resultedin moderate synergism. As expected, the combination of MBV with GCV was antagonistic.CONCLUSIONS: These results suggest that the combination of ART with the antiviral agents tested in this study could be an interesting strategy for the treatment of HCMV infections to reduce toxicity and drug-resistance development.

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PMID: 

Artif Cells Nanomed Biotechnol. 2016 Dec ;44(8):1979-1987. Epub 2016 Jan 11. PMID: 26754823

Abstract Title: 

Enhancing activity of artesunate against breast cancer cells via induced-apoptosis pathway by loading into lipid carriers.

Abstract: 

Artesunate-loaded nanostructured lipid carriers (ART-NLCs) were prepared by hot homogenization followed by ultrasonication technique. The optimized ART-NLC demonstrated a particle size of 117.5 ± 6.1 nm, with good stability regarding zeta-potential of  -19.47 ± 0.9 mV and drug entrapment efficiency of 92.93 ± 1.47%. ART-NLC showed good cellular uptake in breast cancer cells, which was confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry analysis. The significantly higher in vitro cytotoxicity of ART-NLCs against human breast cancer MCF-7, MDA-MB-231 cells as compared with the free ART was recorded.  Hoechst 33342 staining indicated that ART-NLC induced higher apoptosis rates in MCF-7 as well as MDA-MB-231cells than free ART.

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PMID: 

Cancer Chemother Pharmacol. 2018 03 ;81(3):587-596. Epub 2018 Feb 1. PMID: 29392450

Abstract Title: 

A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies.

Abstract: 

PURPOSE: The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).METHODS: Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.RESULTS: A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patientshad stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.CONCLUSION: The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population. CLINICALTRIALS.GOV IDENTIFIER: NCT02353026.

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PMID: 

Exp Cell Res. 2016 10 1 ;347(2):251-60. Epub 2016 Jun 18. PMID: 27327234

Abstract Title: 

Artesunate induces ROS-dependent apoptosis via a Bax-mediated intrinsic pathway in Huh-7 and Hep3B cells.

Abstract: 

Artesunate (ARS), an artemisinin derivative, has been demonstrated to possess antitumor activity in various human tumor cells. This study aims to investigate the molecular mechanism by which ARS induces apoptosis in human hepatocellular carcinoma cells (Huh-7 and Hep3B cells). ARS effectively induced externalization of phosphatidylserine (PS), depolarization of mitochondrial membrane, release of cytochrome c from mitochondria, and activation of caspase-9 and 3, characteristics of the intrinsic apoptosis. Pretreatment with antioxidant N-Acetyle-Cysteine (NAC) completely blocked ARS-induced reactive oxygen species (ROS) generation and apoptosis in the two cell lines. ARS increased cellular iron ions level in Huh-7/Hep3B cells, but decreased cellular iron ions level in HepG2 cells. Pifithrin-alpha (PFT), an inhibitor of p53, significantly enhanced ARS-induced cytotoxicity in HepG2 cells, and the forced expression of wild-type p53 significantly enhanced ARS-induced cytotoxicity in Hep3B cells. In addition, ARS induced translocation and activation of the proapoptotic Bax, and silencing Bax remarkably inhibited ARS-induced apoptosis andΔΨm collapse in Huh-7 and Hep3B cells, demonstrating the key role of Bax in ARS-induced apoptosis. Collectively, our data demonstrate that ARS induces ROS-dependent apoptosis via a Bax-mediated intrinsic pathway in Huh-7 and Hep3B cells.

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PMID: 

J Pharmacol Sci. 2018 Oct ;138(2):131-137. Epub 2018 Sep 29. PMID: 30337244

Abstract Title: 

Artesunate enhances radiosensitivity of esophageal cancer cells by inhibiting the repair of DNA damage.

Abstract: 

Radiotherapy plays an important therapeutic role in esophageal cancer (EC). However, acquired radioresistance impairs the efficacy of radiotherapy, often leading to treatment failure. Therefore, it is important to develop novel radiosensitizers to enhance the clinical treatment of EC. The purpose of this study was to investigate the role of artesunate (ART) on radiosensitivity of human EC cell line TE-1. We found that ART inhibited the proliferation of EC cells and enhanced the radiosensitivity of TE-1 cells (SER = 1.24). In vivo tumor growth of xenografts was inhibited markedly by irradiation (IR) combined with ART, with a tumor inhibition rate of 53.76% in IR + ART group vs. 41.13% in IR-alone group. Pretreatment with ART significantly prompted cell apoptosis and reversed the IR-induced G/M arrest. ART treatment could aggravate DNA damage of EC cells and prolong the formation ofγ-H2AX foci induced by IR. ART up-regulated P21 and down-regulated the expression of cyclin D1, RAD51, RAD54, Ku70 and Ku86 protein of irradiated TE-1 cells. These findings support that ART induce radiosensitivity of TE-1 cells in vitro and in vivo, and may prove to be a promising radiosensitizer for EC treatment.

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PMID: 

Virus Genes. 2016 Feb ;52(1):22-8. Epub 2016 Jan 6. PMID: 26739460

Abstract Title: 

Artesunate, an anti-malarial drug, has a potential to inhibit HCV replication.

Abstract: 

Hepatitis C virus (HCV) infection is a major global health issue. Although the search for HCV treatments has resulted in great achievements, the current treatment methods have limitations, and new methods and drugs for hepatitis C treatment are still required. The aim of the present study was to investigate the effects of artesunate (ART) on HCV replication and compared these effects with those of ribavirin (RBV) and interferon-2b (IFN). The study was performed in HCV-infection cell models (JFH1-infected Huh7.5.1 and OR6 cell lines). Our results showed that the antimalarial drug ART inhibited HCV replicon replication in a dose- and time-dependent manner at a concentration that had no effect on the proliferation of exponentially growing host cells, and the inhibitory effect on HCV replication was stronger than RBV but weaker than IFN, as determined by qPCR, luciferase assays, and Western blot analysis. Furthermore, the combination of ART and IFN resulted in a greater inhibition of HCV replication. These findings demonstrated that ART had an inhibitive effect on HCV replication and may be a novel supplemental co-therapy with IFN and RBV for HCV and as an alternative strategy to combat resistance mechanisms that have emerged in the presence of DAA agents.

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PMID: 

Zhongguo Zhong Yao Za Zhi. 2018 Feb ;43(4):772-778. PMID: 29600654

Abstract Title: 

[Artesunate inhibits proliferation of glioblastoma cells by arresting cell cycle].

Abstract: 

Glioblastoma is a common brain tumor and the overall survival rate of the patients is very low, so it is an effective way to develop the potential chemotherapy or adjuvant chemotherapy drugs in glioblastoma treatment. As a well-known antimalarial drug, artesunate(ARTs) has clear side effects, and recently it has been reported to have antitumor effects, but rarely reported in glioblastoma. Different concentrations of ARTs were used to treat the glioblastoma cells, and then the inhibitory effect of ARTs on glioblastoma proliferation was detected by MTT assay; Ki67 immunofluorescence assay was used to detect the proliferation of cells; Soft agar experiment was used to explain the clonal formation abilities; Flow Cytometry was used to detect the cell cycle; and Western blot assay was used to determine the expression of key cell cycle protein. MTT assay results indicated that ARTs-treated glioblastoma cell A172, U251, U87 were significantly inhibited in a time-and-dose dependent manner as compared to the control group(DMSO treatment group). Soft agar experiment showed that ARTs could significantly reduce the clonal formation ability of glioblastoma. Furthermore, Flow cytometry analysis showed that ARTs could obviously increase the cell proportion in G₀/G₁ phase and reduce the cell proportion in S phase. Western blot results showed that the expressions of cell cycle-related proteins CDK2, CDK4, cyclin D1 and cyclin B1 were all obviously down-regulated. Above all, ARTs may inhibit the proliferation of glioblastoma cells by arresting cell cyclein G₀/G₁ phase through down-regulating the expression of CDK2, CDK4, cyclin D1, cyclin B1. These results may not only provide a novel method for rediscovering and reusing ARTs but also provide a new potential drug for treating glioblastoma.

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