Anticancer Targets and Signaling Pathways Activated by Britannin and Related Pseudoguaianolide Sesquiterpene Lactones

Abstract

Sesquiterpene lactones (SLs) are abundant in plants and display a large spectrum of bioactivities. The compound britannin (BRT), found in different Inula species, is a pseudoguaianolide-type SL equipped with a typical and highly reactive α-methylene-γ-lactone moiety. The bioproperties of BRT and related pseudoguaianolide SLs, including helenalin, gaillardin, bigelovin and others, have been reviewed. Marked anticancer activities of BRT have been evidenced in vitro and in vivo with different tumor models. Three main mechanisms are implicated: (i) interference with the NFκB/ROS pathway, a mechanism common to many other SL monomers and dimers; (ii) blockade of the Keap1-Nrf2 pathway, with a covalent binding to a cysteine residue of Keap1 via the reactive α-methylene unit of BRT; (iii) a modulation of the c-Myc/HIF-1α signaling axis leading to a downregulation of the PD-1/PD-L1 immune checkpoint and activation of cytotoxic T lymphocytes. The non-specific reactivity of the α-methylene-γ-lactone moiety with the sulfhydryl groups of proteins is discussed. Options to reduce or abolish this reactivity have been proposed. Emphasis is placed on the capacity of BRT to modulate the tumor microenvironment and the immune-modulatory action of the natural product. The present review recapitulates the anticancer effects of BRT, some central concerns with SLs and discusses the implication of the PD1/PD-L1 checkpoint in its antitumor action.

Telomerase: a nexus between cancer nanotherapy and circadian rhythm

“…It directly or indirectly associates with NF-κB, inhibiting the release of NF-κB dimers and their translocation into the nucleus for oncogenic transcription regulation. 83 In rhabdomyosarcoma, helenalin induces cell cycle arrest in the G2/M phase. 84 For ovarian cancer and leukemia, helenalin targets NF-κB p65 expression, inhibiting the transcription of oncogenic factors associated with cancer progression.…”

Britanin – a beacon of hope against gastrointestinal tumors?

“…Regardless of the topic, any studies of the relationship between Britanin and its influence on signaling pathways or the proteome should be supported by molecular docking. Existing data indicates that Britanin interacts with such essential proteins as NF-κB, PD-L1, Myc, and HIF-1α[ 4 , 12 , 23 , 46 ], and it may also influence other important proteins and pathways, such as BCL-2, BAX, AMPK, MMP-9, TWIST-1, COX-2, or PPARγ.…”

Isolation and NMR Scaling Factors for the Structure Determination of Lobatolide H, a Flexible Sesquiterpene from Neurolaena lobata

“…An important structural feature of the SLs is the presence of a γ -lactone ring containing in many cases an α -methylene group. The biological activity (e.g., cytotoxic [ 1 , 5 , 6 , 7 , 8 ], anti-inflammatory [ 2 , 9 , 10 , 11 ]) of SLs is mainly due to the presence of this structural element [ 12 , 13 , 14 ]. Furthermore, there are also reports on neuroprotective [ 15 , 16 ], antimicrobial [ 17 ] or antiparasitic [ 18 , 19 ] activities of SL derivatives.…”