Natural Products and their Derivatives as Immune Check Point Inhibitors: Targeting Cytokine/Chemokine Signalling in Cancer.

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.

Advances in plant-derived natural products for antitumor immunotherapy.

Panaxadiol inhibits IL-1β secretion by suppressing zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages.

Panaxadiol inhibits IL-1β secretion by suppressing zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages

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.

Myong Hak Ri

Papers

Development of natural products for anti-PD-1/PD-L1 immunotherapy against cancer.