Sesquiterpene Lactones in Cancer Therapeutics

Sesquiterpene lactones are a diverse class of plant-derived terpenoids distinguished by a fifteen-carbon backbone and a characteristic α-methylene-γ-lactone moiety. These compounds have attracted considerable attention for their multifaceted anticancer activities, which include induction of programmed cell death, arrest of cell-cycle progression, inhibition of tumour cell migration and modulation of key signalling cascades. In vitro and in vivo studies have demonstrated that sesquiterpene lactones can trigger apoptosis through both intrinsic and extrinsic pathways, often via generation of reactive oxygen species and upregulation of death receptors. They have also been shown to suppress pro-survival transcription factors such as NF-κB and STAT3, thereby sensitising malignant cells to standard chemotherapeutics. Despite promising bioactivities, clinical translation is hindered by low aqueous solubility and rapid metabolic clearance. Contemporary strategies to overcome these limitations include nanoparticle-mediated delivery, prodrug design and structural optimisation guided by structure–activity relationship analyses. Globally, sesquiterpene lactones derived from genera such as Inula, Artemisia and Tanacetum are under active investigation as lead compounds or adjuvants aimed at reducing chemoresistance and improving therapeutic indices in solid tumours and haematological malignancies.

Research from Nature Portfolio

Recent studies have demonstrated that bigelovin, a eudesmanolide sesquiterpene lactone isolated from Inula helianthus aquatica, exerts potent antitumour effects in colorectal cancer models. In vitro, bigelovin suppressed proliferation and colony formation in human colorectal lines by inducing G2/M cell-cycle arrest, elevating reactive oxygen species and upregulating death receptor 5 to trigger apoptosis. In murine xenograft experiments, systemic administration of bigelovin markedly inhibited tumour growth with fewer adverse effects than conventional FOLFOX chemotherapy. Mechanistic insights revealed activation of caspase cascades and DNA damage responses, highlighting bigelovin’s potential as a lead compound for targeted therapy in colorectal malignancies.

Sesquiterpene Lactones in Cancer Therapeutics publication trend

The graph below shows the total number of articles in sesquiterpene lactones in cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Sesquiterpene lactone: A class of naturally occurring terpenoids with a 15-carbon framework and a reactive lactone ring that often confers cytotoxic properties.

Apoptosis: Programmed cell death characterised by caspase activation, DNA fragmentation and membrane blebbing, essential for removal of damaged or unwanted cells.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen that can induce cellular damage and trigger apoptosis when produced in excess.

Death receptor 5 (DR5): A cell-surface receptor that, upon activation by its ligand, initiates the extrinsic apoptotic pathway through caspase-8 activation.

Structure–activity relationship (SAR): Analysis of how chemical modifications to a molecule affect its biological activity, guiding optimisation of potency and selectivity.

G2/M cell-cycle arrest: A checkpoint blockade that prevents cells from entering mitosis, often exploited by anticancer agents to halt proliferation.

References

1. Bigelovin triggered apoptosis in colorectal cancer in vitro and in vivo via upregulating death receptor 5 and reactive oxidative species. Scientific Reports (2017).
2. Research progress on antitumor mechanisms and molecular targets of Inula sesquiterpene lactones. Chinese Medicine (2023).
3. Secondary Metabolites from Inula britannica L. and Their Biological Activities. Molecules (2010).