Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

Qiu, Feifei; Liu, Junfeng; Mo, Xiumei; Liu, Huazhen; Chen, Yuchao; Dai, Zhenhua

doi:10.3389/fimmu.2021.751772

Cited by 18 publications

(11 citation statements)

References 78 publications

(92 reference statements)

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“…Previous reports showed that ART could induce tumor cell apoptosis and ferroptosis by ferrous iron-dependent ROS-triggered ER stress [45]. In addition, ART promotes the tumor cytotoxicity of T, γδT, and NK cells but lowers Treg and MDSC frequencies in tumor-bearing mice [37,46]. In our study, ART treatment decreases MDSC accumulation through DR5induced apoptosis in MDSCs.…”

Section: Discussionsupporting

confidence: 69%

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Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

Zhang

Wang

Wan

et al. 2022

Journal of Immunology Research

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Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy.

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Section: Discussionsupporting

confidence: 69%

“…Recent reports showed that ARTs also have antitumor and immunomodulatory effects, which indicates the potential option for cancer treatment [37]. ART could reduce MDSC levels and enhance the antitumor immune response in 4T1 breast tumor model in vitro and in vivo [38].…”

Section: Introductionmentioning

confidence: 99%

Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

Zhang

Wang

Wan

et al. 2022

Journal of Immunology Research

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“…The mechanism of action of artemisinin is pluri-factorial. It implicates a carbon radical and heme, but also interaction and interference with plasmodial proteins such as the sarcoplasmic endoplasmic calcium ATPase (SERCA), as well as an induced immunoregulation [ 124 , 125 , 126 ]. A similar complexity can be anticipated with yingzhaosu A.…”

Section: Mechanism Of Action Of Yingzhaosu Amentioning

confidence: 99%

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Bailly

Hénichart

2022

Molecules

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The medicinal plant Artabotrys hexapetalus (synonyms: A. uncinatus and A. odoratissimus) is known as yingzhao in Chinese. Extracts of the plant have long been used in Asian folk medicine to treat various symptoms and diseases, including fevers, microbial infections, ulcers, hepatic disorders and other health problems. In particular, extracts from the roots and fruits of the plant are used for treating malaria. Numerous bioactive natural products have been isolated from the plant, mainly aporphine (artabonatines, artacinatine) and benzylisoquinoline (hexapetalines) alkaloids, terpenoids (artaboterpenoids), flavonoids (artabotrysides), butanolides (uncinine, artapetalins) and a small series of endoperoxides known as yingzhaosu A-to-D. These natural products confer antioxidant, anti-inflammatory and antiproliferative properties to the plant extracts. The lead compound yingzhaosu A displays marked activities against the malaria parasites Plasmodium falciparum and P. berghei. Total syntheses have been developed to access yingzhaosu compounds and analogues, such as the potent compound C14-epi-yingzhaosu A and simpler molecules with a dioxane unit. The mechanism of action of yingzhaosu A points to an iron(II)-induced degradation leading to the formation of two alkylating species, an unsaturated ketone and a cyclohexyl radical, which can then react with vital parasitic proteins. A bioreductive activation of yingzhaosu A endoperoxide can also occur with the heme iron complex. The mechanism of action of yingzhaosu endoperoxides is discussed, to promote further chemical and pharmacological studies of these neglected, but highly interesting bioactive compounds. Yingzhaosu A/C represent useful templates for designing novel antimalarial drugs.

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“…Several semi-synthetic derivative drugs have been obtained from ART: artemether, artemisone, artesunate (AS), artefenomel (OZ439) and artenimol or dihydroartemisinin (i.e., the active metabolite of ART). These drugs have been widely repurposed to treat several diseases including viral infections [ 121 , 122 , 123 ].…”

Section: Antimalarial Drugsmentioning

confidence: 99%

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey

et al. 2022

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More than two years have passed since the viral outbreak that led to the novel infectious respiratory disease COVID-19, caused by the SARS-CoV-2 coronavirus. Since then, the urgency for effective treatments resulted in unprecedented efforts to develop new vaccines and to accelerate the drug discovery pipeline, mainly through the repurposing of well-known compounds with broad antiviral effects. In particular, antiparasitic drugs historically used against human infections due to protozoa or helminth parasites have entered the main stage as a miracle cure in the fight against SARS-CoV-2. Despite having demonstrated promising anti-SARS-CoV-2 activities in vitro, conflicting results have made their translation into clinical practice more difficult than expected. Since many studies involving antiparasitic drugs are currently under investigation, the window of opportunity might be not closed yet. Here, we will review the (controversial) journey of these old antiparasitic drugs to combat the human infection caused by the novel coronavirus SARS-CoV-2.

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Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

Cited by 18 publications

References 78 publications

Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

Advocacy for the Medicinal Plant Artabotrys hexapetalus (Yingzhao) and Antimalarial Yingzhaosu Endoperoxides

Antiparasitic Drugs against SARS-CoV-2: A Comprehensive Literature Survey

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