Sesquiterpene Lactones and Their Antineoplastic Mechanisms

Sesquiterpene lactones are a diverse class of plant-derived secondary metabolites characterised by a 15-carbon skeleton often incorporating an α-methylene-γ-lactone moiety. These compounds exert antineoplastic effects through multiple mechanisms, including induction of apoptosis, disruption of cell cycle progression, inhibition of pro-survival signalling and modulation of redox homeostasis. Many sesquiterpene lactones generate reactive oxygen species (ROS) that perturb mitochondrial integrity and trigger intrinsic apoptotic cascades characterised by mitochondrial outer membrane permeabilisation and caspase activation. In parallel, they can engage extrinsic death receptor pathways and suppress key oncogenic kinases such as AKT, STAT3 and NF-κB. Specific compounds, notably costunolide and dehydrocostuslactone, have advanced into preclinical models where they arrest tumours in G2/M phase, downregulate anti-apoptotic BCL-2 family members and enhance p53 stability. Beyond direct cytotoxicity, these agents alter the tumour microenvironment and inhibit angiogenesis and metastasis. Growing evidence also supports the use of sesquiterpene lactones in combination therapies, where they sensitize cancer cells to radiotherapy and conventional chemotherapeutics and overcome drug resistance by targeting mitophagy and signalling adaptors. The global significance of this class lies in its broad-spectrum activity against solid tumours and haematological malignancies, coupled with a favourable toxicity profile in normal cells. Ongoing research aims to optimise bioavailability, clarify structure–activity relationships and explore synthetic derivatives for clinical translation.

Research from Nature Portfolio

Recent studies have elucidated the synergistic action of costunolide and dehydrocostuslactone in breast cancer models. Proteomic profiling revealed modulation of 14-3-3-mediated signalling, c-Myc-dependent apoptosis pathways and protein kinase A cascades. This combination induced dose-dependent cell cycle arrest at G1/S and G2/M checkpoints, upregulated p53 and phosphorylated 14-3-3 proteins while concurrently downregulating c-Myc, phosphorylated AKT and BID. The altered BAX/BCL-2 ratio facilitated mitochondrial permeabilisation and downstream caspase activation. Collectively, these findings define a multi-targeted mechanism whereby two sesquiterpene lactones cooperatively inhibit breast tumour growth and suggest their potential as adjuvants to existing therapies.

Sesquiterpene Lactones and Their Antineoplastic Mechanisms publication trend

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

Technical terms

Apoptosis: Programmed cell death characterised by caspase activation and DNA fragmentation.

Reactive oxygen species (ROS): Chemically reactive molecules that can induce oxidative damage and trigger cell death pathways.

Cell cycle arrest: Halting of cell division often at G1/S or G2/M checkpoints to prevent proliferation.

Mitochondrial outer membrane permeabilisation (MOMP): A critical event in intrinsic apoptosis leading to cytochrome c release and caspase activation.

Mitophagy: Selective autophagic clearance of damaged mitochondria that can modulate sensitivity to cytotoxic agents.

AKT: A serine/threonine kinase promoting cell survival and growth, often hyperactivated in cancer.

14-3-3 proteins: Regulatory adaptors that interact with phosphorylated targets to control cell cycle and apoptosis.

c-Myc: Oncogenic transcription factor that drives cell proliferation and growth.

p53: Tumour suppressor protein that induces cell cycle arrest or apoptosis in response to DNA damage.

References

1. Investigation of Molecular Mechanisms Involved in Sensitivity to the Anti-Cancer Activity of Costunolide in Breast Cancer Cells. International Journal of Molecular Sciences (2023).
2. Sesquiterpene lactones as emerging biomolecules to cease cancer by targeting apoptosis. Frontiers in Pharmacology (2024).
3. Naturally Isolated Sesquiterpene Lactone and Hydroxyanthraquinone Induce Apoptosis in Oral Squamous Cell Carcinoma Cell Line. Cancers (2023).
4. Costunolide and dehydrocostuslactone combination treatment inhibit breast cancer by inducing cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 pathway. Scientific Reports (2017).
5. Two Naturally Occurring Terpenes, Dehydrocostuslactone and Costunolide, Decrease Intracellular GSH Content and Inhibit STAT3 Activation. PLOS ONE (2011).
6. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells. Radiation Oncology (2011).