Lessons learned from the discovery and development of the sesquiterpene lactones in cancer therapy and prevention

ABSTRACT

Introduction

Sesquiterpene lactones (SLs) are one of the most diverse bioactive secondary metabolites found in plants and exhibit a broad range of therapeutic properties . SLs have been showing promising potential in cancer clinical trials, and the molecular mechanisms underlying their anticancer potential are being uncovered. Recent evidence also points to a potential utility of SLs in cancer prevention.

Areas covered

This work evaluates SLs with promising anticancer potential based on cell, animal, and clinical models: Artemisinin, micheliolide, thapsigargin dehydrocostuslactone, arglabin, parthenolide, costunolide, deoxyelephantopin, alantolactone, isoalantolactone, atractylenolide 1, and xanthatin as well as their synthetic derivatives. We highlight actionable molecular targets and biological mechanisms underlying the anticancer therapeutic properties of SLs. This is complemented by a unique assessment of SL mechanisms of action that can be exploited in cancer prevention. We also provide insights into structure-activity and pharmacokinetic properties of SLs and their potential use in combination therapies.

Expert opinion

We extract seven major lessons learned and present evidence-based solutions that can circumvent some scientific limitations or logistic impediments in SL anticancer research. SLs continue to be at the forefront of cancer drug discovery and are worth a joint interdisciplinary effort in order to leverage their potential in cancer therapy and prevention.

KEYWORDS:

• Animal models
• cancer
• clinical trials
• prevention
• sesquiterpene lactones
• therapy

Article highlights

• Sesquiterpene lactones are plant-derived secondary metabolites currently at the frontline of cancer drug discovery and development.

• Artemisinin, micheliolide, thapsigargin dehydrocostuslactone, arglabin, parthenolide, costunolide, deoxyelephantopin, alantolactone, isoalantolactone, atractylenolide 1, and xanthatin as well as their synthetic derivatives exert promising anticancer therapeutic properties through targeting diverse oncogenic and tumor suppressor gene pathways with limited adverse effects in animal models.

• Sesquiterpene lactones exert chemopreventive properties through inhibiting tumor promotion and underlying multiple signaling pathways.

• Many sesquiterpene lactones advanced to phase 1 and 2 clinical trials.

• We extract seven major lessons learned and present evidence-based solutions that can circumvent some limitations in sesquiterpene lactone research and anticancer potential.

Abbreviations

AKT Protein kinase B; AML Acute myelogenous leukemia; AP-1 Activator protein-1; ARE Antioxidant response element; CAF Cancer associated fibroblasts; COX-2 Cyclooxygenase-2; CRC Colorectal cancer; CSC Cancer stem cell; DMAPT Dimethylamino-parthenolide; DMBA 7,12-dimethylbenz[a]anthracene; ER Endoplasmic reticulum; ERK Extracellular signal-regulated kinases; EZH2 Zeste homolog 2 gene; G-actin Globular actin; GPX4 Glutathione peroxidase 4; GST Glutathione S-transferase; HO-1 Heme oxygenase-1; HOTAIR HOX transcript antisense RNA; IFN-γ Interferon gamma; JB6P+ JB6 model of tumor promotion; JNK c-Jun N-terminal kinase; 15-LO 15-Lipoxygenase; MAPK Mitogen-activated protein kinases; MGMT O(6)-methylguanine-DNA-methyltransferase; MMP Matrix metalloproteinase; MNU N-methyl-N-nitroso-urea; mTOR Mammalian target of rapamycin; NF-κB Nuclear factor kappa B; NOTCH1 Mutated neurogenic locus notch homolog protein; NQO-1 NAD(P)H quinone dehydrogenase 1; Nrf2 Nuclear factor erythroid 2-related factor 2; PDCD4 Programmed cell death 4; PDK1 3-phosphoinositide dependent protein kinase-1; PDXM Patient derived xenograft model; PEBP1 phosphatidylethanolamine-binding protein; PI3K Phosphoinositide 3-kinase; PKM2 Pyruvate kinase 2; QR NAD(P)H:quinone reductase; ROS Reactive oxygen species; SERCA Sarco/endoplasmic calcium-transporting ATPases; SL Sesquiterpene lactone; STAT3 Signal transducer and activator of transcription 3; TGF-β Transforming growth factor β; TNF-α Tumor necrosis factor α; TrxR1 Thioredoxin reductase 1; UVB Ultraviolet-B; VGEF Vascular endothelial growth factor; YAP1 Yes-associated protein 1; γ-GCS γ-Glutamylcysteine synthetase

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

^† Disclaimer

Where authors are identified as personnel of the International Agency for Research on Cancer/ World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/ World Health Organization.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460441.2023.2147920

Additional information

Funding

This paper was not funded.