Sesquiterpene lactones are a large class of secondary metabolites, most of which are derived from plants in the Asteraceae family. They possess various biological activities, including antitumor, anti-inflammatory, and antibacterial effects. Based on the carboxyl skeleton, types, and positions of substituents, sesquiterpene lactones can be divided into germacranolides, guaianolides, pseudoguaianolides, eudesmanolides, elemanolides, etc. In recent years, sesquiterpene lactones with antitumor activity have been mainly found in artemisinin, inula lactones, elephantopus lactones, centipedegrass lactones, and feverfew lactones. Artemisinin is a sesquiterpene lactone compound found in Artemisia annua, and its derivatives, dihydroartemisinin and artemisinin esters, have significant inhibitory effects on various tumors. Inula lactones, including inula lactone, isoinula lactone, costunolide, and dehydrocostus lactone, have been found to have antitumor activity in Inula helenium L. Elephantopus lactones, such as deoxyelephantopin, isodeoxyelephantopin, and elephantopin, have been found to have antitumor activity in Elephantopus scaber L. Centipedegrass lactones, such as centipedegrass lactone D and parthenolide, have been found to have antitumor activity in Centipeda minima L. Feverfew lactones, including parthenolide, dimethylaminoparthenolide, uvarigran, epoxymicheliolide, and dimethylaminomicheliolide, have been found to have antitumor activity in Tanacetum parthenium L. Moreover, sesquiterpene lactones isolated from other plants also exhibit tumor inhibitory effects. For example, the compound britannin, isolated from Inula aucheriana, has inhibitory effects on most tumor cells. Sesquiterpene lactones from Atractylodes macrocephala, such as atractylenolide I and atractylenolide II, have antitumor effects. Hemistepsin A from Hemistepta lyrata Bunge, xanthatin from Xanthium strumarium L., tagitinin C from Tithonia diversifolia A. Gray, toxic carotenoids from Thapsia garganica L., antrocin from Antrodia cinnamomea, and inuloxin A from Inula oculus-christi also exhibit antitumor activity.
Mechanisms of the antitumor activity of sesquiterpene lactones
The main mechanisms of the antitumor activity of sesquiterpene lactones include oxidative stress, iron-mediated cell death, induction of apoptosis, induction of autophagy, and modulation of immune response.
Oxidative stress
Sesquiterpene lactones induce the generation of reactive oxygen species (ROS) by inhibiting thioredoxin reductase (TrxR1) or nuclear factor erythroid 2-related factor 2 (Nrf2). Costunolide induces ROS production and activates the MAPK pathway, leading to apoptosis in gastric cancer cells BGC-823 and SGC-7901 by inhibiting TrxR1 activity. Costunolide inhibits the viability of triple-negative breast cancer cells MDAMB-231 through ROS accumulation and endoplasmic reticulum stress. Additionally, costunolide downregulates Nrf2 expression, induces ROS accumulation, and promotes apoptosis in esophageal adenocarcinoma cells KYAE-1.
Ferroptosis
Ferroptosis is an iron-dependent regulated form of cell death triggered by the toxic accumulation of lipid peroxides on the cell membrane. Artemisinin and dihydroartemisinin downregulate the core negative regulator of ferroptosis, cystine/glutamate transporter (xCT), and upregulate the mRNA levels of transferrin receptor (TFRC), inducing ferroptosis in non-small cell lung cancer cells A549. Deoxyelephantopin and its derivative DETD-35 reshape glutathione and primary metabolism, lipid/oxygen lipid metabolism, and cause mitochondrial damage, leading to lipid ROS accumulation and triggering ferroptosis in melanoma cells A375 and A375-R.
Induction of apoptosis
Apoptosis is the most important pathway for programmed cell death in tumor cells. Most sesquiterpene lactones achieve their antitumor effects by inducing apoptosis in tumor cells. Parthenolide upregulates the expression of apoptosis-inducing factor (AIF) and cytochrome C in liver cancer cells HepG2 and Hepa 1-6, inducing apoptosis. Santamarine activates and stabilizes p53, inducing apoptosis in colon cancer cells ...
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