Development of natural products for anti-PD-1/PD-L1 immunotherapy against cancer.
TL;DR: In this article, the authors summarize natural products, raw extracts, and traditional medicines with pharmacological effects associated with the PD-1/PD-L1 axis, particularly PD-L 1.
About: This article is published in Journal of Ethnopharmacology.The article was published on 2021-06-29. It has received 18 citations till now. The article focuses on the topics: DrugBank.
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TL;DR: In this paper , a review summarises cytokine/chemokine signalling, types of cancer immunotherapy and the herbal medicine-derived natural products targeting cytokine and immune checkpoints.
14 citations
TL;DR: In this article, the authors summarize the progress of comprehensive research on plant-derived natural products and their derivatives and discuss their possible mechanisms in regulating the immune system and their efficacy as monotherapies or in combination with regular chemotherapeutic agents.
Abstract: In recent years, immunotherapy has emerged as a novel antitumor strategy in addition to traditional surgery, radiotherapy and chemotherapy. It uniquely focuses on immune cells and immunomodulators in the tumor microenvironment and helps eliminate tumors at the root by rebuilding the immune system. Despite remarkable breakthroughs, cancer immunotherapy still faces many challenges: lack of predictable and prognostic biomarkers, adverse side effects, acquired treatment resistance, high costs, etc. Therefore, more efficacious and efficient, safer and cheaper antitumor immunomodulatory drugs have become an urgent requirement. For decades, plant-derived natural products obtained from land and sea have provided the most important source for the development of antitumor drugs. Currently, more attention is being paid to the discovery of potential cancer immunotherapy modulators from plant-derived natural products, such as polysaccharides, phenols, terpenoids, quinones and alkaloids. Some of these agents have outstanding advantages of multitargeting and low side effects and low cost compared to conventional immunotherapeutic agents. We intend to summarize the progress of comprehensive research on these plant-derived natural products and their derivatives and discuss their possible mechanisms in regulating the immune system and their efficacy as monotherapies or in combination with regular chemotherapeutic agents.
8 citations
TL;DR: Zhang et al. as discussed by the authors showed that panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages.
5 citations
TL;DR: In this article , Panaxadiol was shown to suppress ZFP91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages.
5 citations
TL;DR: In this article, the authors performed a docking analysis of pseudoguaianolide-type sesquiterpene lactone (SL) britannin (BRT) to the PD-L1 protein, both in its monomeric and dimeric form, binding at the interface of the two monomers.
Abstract: The pseudoguaianolide-type sesquiterpene lactone (SL) britannin (BRT), found in different Inula species, has been characterized as a potent anticancer agent acting via modulation of the transcription factor NFkB and the Nrf2-Keap1 signaling pathway. In addition, a BRT-induced down-regulation of the immune checkpoint PD-L1 (programmed cell death ligand 1) expressed on cancer cells has been evidenced. Here we have performed a docking analysis of the direct binding of BRT to the PD-L1 protein, both in its monomeric and dimeric state. BRT appears to form stable complexes with PD-L1, with a preference for the dimeric form, binding at the interface of the two monomers. The calculated empirical energy of interaction (ΔE) value reaches -63.1 kcal/mol for the BRT-PD-L1 dimer complex, not far from the value calculated with the reference PD-L1 ligand BMS-202 (ΔE = -73.4 kcal/mol) under identical conditions. We also studied the potential PD-L1 dimer binding of 15 pseudoguaianolide sesquiterpene lactones analogues to BRT, including helenalin, gaillardin, bigelovin, coronopilin, and others. The docking analysis predicted that the SL chamissonolide (CHM) can also form equally stable complexes with PD-L1 dimer (ΔE = -64.8 kcal/mol). Preliminary compound structure-PD-L1 binding relationships have been delineated. This computational study supports the proposed interaction of BRT with PD-L1 and provides a guidance to the design of novel PD-L1 binders incorporating a SL-like tricyclic core unit.
3 citations
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TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.
10,602 citations
TL;DR: It is shown that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer, and it is found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of gly colysis enzymes.
1,983 citations
TL;DR: In this article, the authors summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities, and discuss the potential of using natural products as drug leads.
Abstract: Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities. Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.
1,297 citations
TL;DR: The roles of the PD-1-PD-L1 axis in cancer is reviewed, focusing on recent findings on the mechanisms that regulate PD-L 1 expression at the transcriptional, posttranscriptional, and protein level, to inform the design of more precise and effective cancer immune checkpoint therapies.
1,211 citations
TL;DR: It is shown that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.
Abstract: Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.
1,067 citations