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

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. 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. 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.