Research Progress on the Antitumor Activity of Sesquiterpene Lactone Compounds

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 HCT-15, HCT-116, and DLD1. Isocostunolide upregulates the expression of PDCD4 and downregulates the expression of Bcl-xL and XIAP, inducing apoptosis in esophageal squamous cell carcinoma cells KYSE30. Artemisinin increases the expression of Bax and decreases the expression of Bcl-2, lowering the Bcl-2/Bax ratio and inducing apoptosis in H22 liver cancer cells. Parthenolide induces apoptosis in multiple myeloma cells, while not affecting normal lymphocytes under the same conditions. Parthenolide's apoptotic activity is mediated by oxidative stress in MM cells and is further suggested to be associated with NADPH oxidase activity and the generation of MM cell ROS. Zeaflavin upregulates the expression of p53 and Bax, and downregulates the expression of Bcl-2, leading to a decrease in the Bcl-2/Bax ratio and induction of apoptosis in Hela cells. 

Autophagy

Autophagy can mediate apoptosis and cell cycle arrest. Artemisinin induces autophagy in bladder cancer cells T24 and EJ, followed by activation of apoptosis, involving the AMPK-mTORULK1 pathway. Parthenolide induces autophagy in pancreatic cancer cells Panc-1 and significantly upregulates the expression of p62/SQSTM1, Beclin 1, and LC3Ⅱ, ultimately inducing apoptosis. Artemisinin and dihydroartemisinin block the cell cycle at the G2/M phase and induce autophagy in epithelial ovarian cancer cells SKOV3. 

Bidirectional regulation and immune enhancement

Oral administration of artemisinin to S180 tumor-bearing mice significantly inhibits tumor growth and increases serum IgG antibody levels. It enhances the delayed hypersensitivity reaction induced by 2,4-dinitrofluorobenzene (DNFB) and induces the transformation of lymphocytes into lymphoblasts, immune function. Dihydroartemisinin has a significant inhibitory effect on the proliferation of ConA-induced mouse T cells and acts as a potential immunosuppressant. Isocostunolide exhibits potent inhibitory activity against human liver tumor cells (HLE) proliferation and inhibits the growth of H22 transplantable tumors in mice without reducing the thymus index and spleen index, suggesting its potential to enhance immune function and exert anti-tumor activity.

Combination of sesquiterpene lactones with anticancer drugs

Tumor resistance is a major obstacle in cancer treatment, and increasing evidence suggests that combining natural products with anticancer drugs can achieve better therapeutic effects. Sesquiterpene lactones can be combined with various chemotherapy drugs to inhibit the proliferation of multiple tumor cells, leading to sensitization and synergistic effects. In combination with radiotherapy, parthenolide enhances the inhibitory and apoptotic effects of X-rays on cervical cancer cells HeLa by inhibiting thioredoxin reductase (TrxR) activity and inducing reactive oxygen species (ROS) generation. Dimethylaminomicheliolide enhances the sensitivity of mouse colon cancer cells CT26 and glioblastoma cells GL261 to radiotherapy, inducing ROS generation, cell apoptosis, and DNA double-strand breaks. It also synergizes with anti-PD-L1 antibody (α-PD-L1) to achieve a synergistic anti-tumor effect. Dihydroartemisinin inhibits mitochondrial autophagy and radiation resistance in lung cancer A549 cells by suppressing the expression of cold-inducible RNA-binding protein (CIRBP). Knocking out the CIRBP gene inhibits mitochondrial autophagy and radiation resistance in A549R cells, and combination with dihydroartemisinin further suppresses mitochondrial autophagy and radiation resistance in A549R cells. Antrocin combined with radiotherapy inhibits the proliferation and induces apoptosis in radiation-resistant prostate cancer cell lines (LAPC4-KD and PC3-KD), downregulating the PI3K/AKT and MAPK signaling pathways, regulating the cell cycle, and inducing apoptosis. In combination with immunotherapy, artemisinin sensitizes human chronic myelogenous leukemia K562 cells, lymphoma Raji cells, and mouse lymphoma YAC-1 cells to NK cell-mediated cytotoxicity. β-eudesmol significantly promotes tumor antigen presentation, enhances the cytotoxicity of CD8+ T cells, and improves the response of tumors to immunotherapy in human colorectal cancer cells HCT116, SW837, and mouse colorectal cancer cells MC38 and CT26. Currently, Dimethylaminomicheliolide, based on parthenolide, and Mipsagargin, based on toxicin, both belonging to the sesquiterpene lactone class, have entered clinical trials and have shown great potential. Sesquiterpene lactones not only inhibit drug-resistant tumor cells but also exhibit sensitization and synergistic effects when used in combination with other anticancer drugs. They can increase the sensitivity of cells to chemotherapy drugs, radiotherapy, and immunotherapy, resulting in synergistic effects, enhanced cytotoxicity, and induction of apoptosis. Therefore, the search for new targets for anticancer drug action and the development of natural anticancer drugs can reduce the cost of chemotherapy and alleviate the suffering of cancer patients, allowing more patients to receive timely and effective treatment and improve their quality of life.

Reference:

[1] Zhu, H., & Park, H. (2015). Research progress on the mechanism of anti-tumor action of sesquiterpene lactone compounds. West China Journal of Pharmaceutical Sciences, 30(03), 381-383.

[2] Lin, J., & Chen, S. (2023). Research progress on the anti-tumor activity and mechanism of sesquiterpene lactone compounds. Central South Pharmacy, 21(06), 1589-1598.