Research Progress on the Antitumor Effects of Sesquiterpene Lactones

Sesquiterpene lactones are a large class of secondary metabolites, most of which are derived from Asteraceae plants and possess various biological activities such as anti-tumor, anti-inflammatory, and antibacterial effects. Depending on the carbonyl skeleton, types, and positions of substituents, sesquiterpene lactones can be classified into several subclasses, including germacranolides, guaianolides, pseudoguaianolides, eudesmanolides, and elemanolides.

In recent years, sesquiterpene lactones with antitumor activity have been mainly identified in Artemisinin, Inula helenium L., Elephantopus scaber L., Centipeda minima L., and Tanacetum parthenium L. Artemisinin, a sesquiterpene lactone compound discovered in the Asteraceae plant Artemisia annua L., and its derivatives dihydroartemisinin and artesunate have significant inhibitory effects on various tumors. The antitumor sesquiterpene lactones found in Inula helenium L. mainly include inulin, isoinulin, costunolide, and dehydrocostus lactone. Among those discovered in Elephantopus scaber L., the antitumor sesquiterpene lactones mainly consist of deoxyelephantopin, isodeoxyelephantopin, and elephantopin. In Centipeda minima L., the antitumor sesquiterpene lactones are primarily mountain goldenrod lactone D and centipedin. The antitumor sesquiterpene lactones identified in Tanacetum parthenium L. mainly comprise tanaparthin, dimethylamino-tanaparthin, micheliolide, Epoxymicheliolide, and Dimethylaminomicheliolide.

In addition, sesquiterpene lactones isolated from other plants also exhibit tumor-suppressing effects. For instance, Britannin, a compound isolated from the genus Inula aucheriana, inhibits the growth of most tumor cells. From the traditional Chinese medicine Atractylodes macrocephala, sesquiterpene lactones such as Atractylodin I and Atractylodin II are found. Hemistepsin A is isolated from Hemistepta lyrata Bunge. Xanthium strumarium L., another traditional Chinese medicine, contains xanthin. Tagitinin C, a compound from Tithonia diversifolia A. Gray, also exhibits antitumor properties. The poisonous carrotin from Thapsia garganica L. and Antrocin from Antrodia cinnamomea also possess antitumor effects. Finally, Helichrysin, a sesquiterpene lactone, is isolated from the genus Inula oculus-christi.

The Antitumor Mechanisms of Sesquiterpene Lactones

The antitumor mechanisms of sesquiterpene lactone natural products mainly include oxidative stress, ferroptosis, apoptosis induction, autophagy induction, and immune modulation and enhancement.

1、Oxidative Stress

Sesquiterpene lactones can induce ROS production by inhibiting thioredoxin reductase 1 (TrxR1) or nuclear factor erythroid 2-related factor 2 (Nrf2). In gastric cancer cells BGC-823 and SGC-7901, inulin inhibits the activity of TrxR1, leading to ROS generation, which in turn activates the MAPK pathway and ultimately induces apoptosis of tumor cells. Inulin can also inhibit the activity of triple-negative breast cancer cell line MDAMB-231 through ROS accumulation and endoplasmic reticulum stress. Furthermore, in esophageal adenocarcinoma cell line KYAE-1, inulin downregulates Nrf2 expression, inducing intracellular ROS accumulation, which further triggers cell apoptosis.

2、Ferroptosis

Ferroptosis is an iron-dependent form of regulated cell death triggered by the toxic accumulation of lipid peroxides on the cell membrane. Artemisinin and dihydroartemisinin can downregulate the expression of the key negative regulator of ferroptosis, cystine/glutamate transporter (xCT), and upregulate the mRNA level of the positive regulator of ferroptosis, transferrin receptor (TFRC), in non-small cell lung cancer A549 cells, thereby inducing ferroptosis in A549 cells. Deoxyelephantopin and its derivative DETD-35 can reshape glutathione and primary metabolism, lipid/oxylipid metabolism, and cause mitochondrial damage in melanoma cells A375 and A375-R, leading to lipid ROS accumulation and triggering ferroptosis.

3、Induction of Apoptosis

Apoptosis is the most important pathway for the programmed death of tumor cells. Most sesquiterpene lactones achieve their antitumor effects by inducing tumor cell apoptosis. Wuxinshilactone can upregulate the expression of apoptosis-inducing factor (AIF) and cytochrome C in liver cancer cells HepG2 and Hepa 1-6, leading to apoptosis. Costunolide activates and induces the stability of p53 in colorectal cancer cells HCT-15, HCT-116, and DLD1, thereby inducing apoptosis. Isocostunolide upregulates the expression of PDCD4 and downregulates the expression of Bcl-xL and XIAP in esophageal squamous cell carcinoma cells KYSE30, inducing cell apoptosis. Artesunate can increase the expression of Bax gene, decrease the expression of Bcl-2 gene, and lower the Bcl-2/Bax ratio in solid tumor tissue samples from H22 liver cancer mice, indicating that artesunate can downregulate the expression of PCNA and Bcl-2, upregulate the expression of Bax, and induce cell apoptosis. Parthenolide (PN) can induce apoptosis in multiple myeloma cells, while normal lymphocytes remain unaffected under the same conditions. The apoptotic activity of PN is mediated by causing oxidative stress in MM cells, and it is further speculated that the oxidative activity of NADPH is related to the production of ROS in PN-mediated MM cells. Eupalinstatin upregulates the expression of p53 and Bax in Hela cells, downregulates the expression of Bcl-2, reduces the Bcl-2/Bax ratio, and induces cell apoptosis.

4、Cellular Autophagy

Cellular autophagy can mediate apoptosis and cell cycle arrest. For example, artesunate can induce autophagy in bladder cancer cells T24 and EJ, followed by the activation of apoptosis, with the AMPK-mTOR-ULK1 pathway participating in the autophagy and apoptosis process. Parthenolide in pancreatic cancer cells Panc-1 can induce tumor cell autophagy and significantly upregulate the expression of p62/SQSTM1, Beclin 1, and LC3-II, ultimately leading to apoptosis. Artemisinin and dihydroartemisinin can arrest the cell cycle in the G2/M phase and induce autophagy in epithelial ovarian cancer cells SKOV3.

5、Bidirectional Regulation and Immune Enhancement

Administering artesunate via gastric gavage to S180 tumor-bearing mice at doses of 60, 30, and 15 g·kg-1·d-1 significantly inhibited the growth of S180 tumors and increased the serum IgG antibody level in S180 tumor-bearing mice. It also enhanced the delayed-type hypersensitivity reaction induced by 2,4-dinitrofluorobenzene (DNFB) and induced the transformation of lymphocytes into lymphoblasts, improving the immune function of mice. Dihydroartemisinin has a significant inhibitory effect on the proliferation of mouse T cells induced by Concanavalin A (ConA), making it a potential immunosuppressant. Isosafrole has strong inhibitory activity against the proliferation of human liver tumor cells (HLE) and also inhibits the growth of transplanted H22 tumors in mice, without reducing the thymus index and spleen index of tumor-bearing mice. It is speculated that isosafrole achieves its antitumor activity by enhancing the immune capability of the body.

Combination of Sesquiterpene Lactone Compounds with Anticancer Drugs

Tumor resistance is a major obstacle in cancer treatment, and increasing research has shown that combining natural products with anticancer drugs can lead to better therapeutic outcomes. In the combination of sesquiterpene lactone compounds with anticancer drugs, it mainly involves chemotherapy, radiotherapy, and immunotherapy. Sesquiterpene lactone compounds can be used in combination with multiple chemotherapeutic drugs to inhibit the proliferation of various tumor cells, achieving sensitization and synergistic enhancement of effects. In combination with radiotherapy, wuxinshilactone can enhance the inhibitory effect of X-rays on cervical cancer Hela cells and apoptosis induction, inhibit the activity of thioredoxin reductase (TrxR) in HeLa cells, and induce the generation of reactive oxygen species (ROS). Dimethylaminomicheliolide can increase the sensitivity of mouse colorectal cancer cells CT26 and glioblastoma cells GL261 to radiotherapy, induce ROS generation, apoptosis, and DNA double-strand breaks, and can be combined with anti-PD-L1 antibodies (α-PD-L1) to produce synergistic antitumor effects. Dihydroartemisinin can reduce mitochondrial autophagy and radiation resistance in lung cancer A549 cells by inhibiting the expression of cold-inducible RNA-binding protein (CIRBP). Knocking out the CIRBP gene can inhibit mitochondrial autophagy and radiation resistance in A549R cells, and combining it with dihydroartemisinin can further inhibit mitochondrial autophagy and radiation resistance in A549R cells. Antrocin combined with radiotherapy can inhibit the proliferation of prostate cancer DAB2IP gene knockout radioresistant cell lines (LAPC4-KD and PC3-KD) and shControl cell lines (LAPC4-Con and PC3-Con) and induce apoptosis, downregulating the PI3K/AKT and MAPK signaling pathways, regulating the cell cycle, and inducing apoptosis. In combination with immunotherapy, artemisinin can sensitize human chronic myelogenous leukemia K562 cells, lymphoma Raji cells, and mouse lymphoma YAC-1 cells to NK cell-mediated cytolysis. Baizhu lactone I can significantly promote tumor antigen presentation in human colorectal cancer cells HCT116, SW837, and mouse colorectal cancer cells MC38, CT26, enhance the cytotoxic response of CD8+ T cells, and improve the tumor's response to immunotherapy.

Currently, both Dimethylaminomicheliolide synthesized based on parthenolide, a sesquiterpene lactone, and Mipsagargin synthesized based on thapsigargin, another sesquiterpene lactone, have entered clinical trial stages, demonstrating significant potential. Sesquiterpene lactone natural products not only inhibit drug-resistant tumor cells, but also exhibit sensitization and synergistic effects when combined with other drugs. Sesquiterpene lactone compounds can increase cell sensitivity to chemotherapeutic drugs, radiation, and immunotherapy, leading to synergistic effects that enhance cytotoxicity and induce apoptosis. Therefore, searching for new targets for antitumor drugs and developing new natural anticancer drugs can reduce the cost of chemotherapy, alleviate the suffering of cancer patients, enable more cancer patients to receive timely and effective treatment, and improve their quality of life.

References:

[1] Zhu Huaye, Piao Huishun. Research Progress on Antitumor Mechanism of Sesquiterpene Lactone Compounds [J]. West China Journal of Pharmaceutical Sciences, 2015, 30(03): 381-383.

[2] Lin Jinrong, Chen Sibao. Research Progress on Antitumor Activity and Mechanism of Sesquiterpene Lactone Natural Products [J]. Central South Pharmacy, 2023, 21(06): 1589-1598.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.