A review on the research progress of traditional Chinese medicine with anti-cancer effect targeting ferroptosis.

Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron-dependent lipid peroxidation. It can be triggered by various mechanisms, including the glutathione peroxidase 4 (GPX4)-glutathione (GSH) axis, iron metabolism, lipid metabolism, the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, and the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 axis. The redox balance is disrupted when ferroptosis occurs in cells, which is fatal to cancer cells. Additionally, some tumor-associated genes are involved in ferroptosis. Hence, targeting ferroptosis might be an effective strategy for treating cancer. Several small-molecule compounds exhibit anti-tumor effects through ferroptosis, including sorafenib and altretamine, which induce ferroptosis by inhibiting System-Xc and GPX4 respectively, but many problems, such as poor druggability, still exist. Some studies have shown that many traditional Chinese medicine (TCM) induce ferroptosis by inhibiting GPX4, solute carrier family 7 member 11 (SLC7A11), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2), or by increasing the expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4), transferrin (TF), and transferrin receptor 1 (TFR1). These changes can lead to the lysosomal degradation of ferritin, accumulation of iron, lipid peroxidation and the production of reactive oxygen species (ROS), which in turn can promote anti-tumor activities or synergistic effects with chemotherapeutic drugs. In this study, we elucidated the underlying mechanisms of ferroptosis, and the anti-tumor pharmacology of TCM targeting ferroptosis including prescriptions, Chinese herbs, extracts, and natural compounds. Our findings might act as valuable reference for research on anti-tumor drugs targeting ferroptosis, especially those drugs developed from TCM.

Seven new 3,4-dihydro-furanocoumarin derivatives from Angelica dahurica.

Objective: To study the chemical constituents of the roots of Angelica dahurica, a well-known Chinese herbal medicine named Baizhi in Chinese. Methods: Compounds were separated by various chromatographies, and the structures of new compounds were elucidated based on the analysis of their spectroscopic and spectrometric data (1D, 2D NMR, HRESI MS, IR, and UV). The absolute configurations of new compounds were determined by the calculated electronic circular dichroism and chemical derivatization. The inhibitory activities of all isolates against nitric oxide (NO) production were evaluated using lipopolysaccharide-activated RAW 264.7 macrophage cells. Results: Seven new 3,4-dihydro-furanocoumarin derivatives (1a/1b, 2a/2b, 3a/3b, 4) together with a known furanocoumarin (5) were isolated from the roots of A. dahurica. The new compounds included three pairs of enantiomers, (4S, 2''R)-angelicadin A (1a)/(4R, 2''S)-angelicadin A (1b), (4S, 2''S)-angelicadin A (2a)/(4R, 2''R)-angelicadin A (2b), and (4S, 2''S)-secoangelicadin A (3a)/(4R, 2''R)-secoangelicadin A (3b), together with (4R, 2''R)-secoangelicadin A methyl ester (4). The known xanthotoxol (5) inhibited the NO production with the half-maximal inhibitory concentration (IC50) value of (32.8 ± 0.8) µmol/L, but all the new compounds showed no inhibitory activities at the concentration of 100 µmol/L. Conclusion: This is the first report of the discovery of 3,4-dihydro-furanocoumarins from A. dahurica. The results are not only meaningful for the understanding of the chemical constituents of A. dahurica, but also enrich the reservoir of natural products.

The Role of Traditional Chinese Medicine in Cancer Immunotherapy: Current Status and Future Directions.

The tumor microenvironment (TME) plays an important role in the development of tumors. Immunoregulatory cells and cytokines facilitate cancer cells to avoid immune surveillance. Overexpression of immune checkpoint molecules such as CTLA-4 and PD-1/PD-L1 inhibits immune function and enables cancer cells to avoid clearance by the immune system. Thus, minimizing tumor immunosuppression could be an important strategy for cancer therapy. Currently, many immune checkpoint-targeted drugs, such as PD-1/PD-L1 inhibitors, have been approved for marketing and have shown unique advantages in the clinical treatment of cancers. The concept of "strengthening resistance to eliminate pathogenic factors" in traditional Chinese medicine (TCM) is consistent with the immunotherapy of cancer. According to previous studies, the role of TCM in tumor immunotherapy is mainly associated with the positive regulation of natural killer cells, CD8/CD4 T cells, dendritic cells, M2 macrophages, interleukin-2, tumor necrosis factor-[Formula: see text], and IFN-[Formula: see text], as well as with the negative regulation of Tregs, myeloid-derived suppressor cells, cancer-associated fibroblasts, PD-1/PD-L1, transforming growth factor-[Formula: see text], and tumor necrosis factor-[Formula: see text]. This paper summarizes the current research on the effect of TCM targeting the TME, and further introduces the research progress on studying the effects of TCM on immune checkpoints. Modern pharmacological studies have demonstrated that TCM can directly or indirectly affect the TME by inhibiting the overexpression of immune checkpoint molecules and enhancing the efficacy of tumor immunotherapy. TCM with immunomodulatory stimulation could be the key factor to achieve benefits from immunotherapy for patients with non-inflammatory, or "cold", tumors.

DHMMF, a natural flavonoid from Resina Draconis, inhibits hepatocellular carcinoma progression via inducing apoptosis and G2/M phase arrest mediated by DNA damage-driven upregulation of p21.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is extremely malignant in nature. It is an important way to discover anti-cancer drugs from natural products at present. (R)-7,3'-dihydroxy-4'-methoxy-8-methylflavane (DHMMF), a natural flavonoid, was isolated from Resina Draconis which is the red resin from Dracaena cochinchinensis (Lour.) S. C. Chen. However, the anti-hepatoma effect and underlying mechanisms of DHMMF remain unclear. Herein, we demonstrated that DHMMF treatment significantly inhibited the proliferation of human hepatoma HepG2 and SK-HEP-1 cells. The IC50 value of DHMMF for HepG2 and SK-HEP-1 cells were 0.67 µM and 0.66 µM, respectively, while the IC50 value of DHMMF for human normal liver LO2 cells was 120.60 µM. DHMMF induced DNA damage, apoptosis, and G2/M phase arrest in HepG2 and SK-HEP-1 cells. Furthermore, the anti-proliferative and pro-apoptotic effects of DHMMF in human hepatoma cells were mediated by the upregulation of p21. Importantly, DHMMF exhibited potent anti-HCC efficacy in a xenograft mice model and an orthotopic mice model of liver cancer. Additionally, the combined administration of DHMMF and polo-like kinase 1 (PLK1) inhibitor BI 6727 showed a synergistic anti-HCC efficacy. Collectively, we demonstrated that DHMMF treatment induced apoptosis and G2/M phase arrest via DNA damage-driven upregulation of p21 expression in human hepatoma cells. DHMMF may serve as a promising drug candidate for HCC treatment, especially for patients of HCC with low p21 expression. Our results also suggested that DHMMF treatment in combination with PLK1 inhibitor may serve as a potential treatment strategy for patients with HCC.

Chinese dragon's blood ethyl acetate extract suppresses gastric cancer progression through induction of apoptosis and autophagy mediated by activation of MAPK and downregulation of the mTOR-Beclin1 signalling cascade.

Gastric cancer (GC) is a malignancy with high morbidity and mortality. Chinese dragon's blood is a traditional Chinese medicine derived from the red resin of Dracaena cochinchinensis (Lour.) S. C. Chen. However, the antigastric cancer effect of Chinese dragon's blood has not yet been reported. Herein, we demonstrated that Chinese dragon's blood ethyl acetate extract (CDBEE) suppressed the proliferative and metastatic potential of human gastric cancer MGC-803 and HGC-27 cells. CDBEE suppressed epithelial-mesenchymal transition in MGC-803 and HGC-27 cells. Moreover, CDBEE induced apoptotic and autophagic cell death in MGC-803 and HGC-27 cells. The cytotoxicity of CDBEE in human gastric epithelial GES-1 cells was dramatically weaker than that in human gastric cancer cells. Mechanistically, the activation of the mitogen-activated protein kinase (MAPK) signalling pathway was involved in the growth inhibition of MGC-803 and HGC-27 cells by CDBEE. Additionally, CDBEE-induced autophagic cell death was mediated by downregulation of the mammalian target of rapamycin (mTOR)-Beclin1 signalling cascade and upregulation of the ATG3/ATG7-LC3 signalling cascade. Importantly, CDBEE exhibited potent anti-GC efficacy in vivo without obvious toxicity or side effects. Therefore, CDBEE may be a promising candidate drug for the treatment of gastric cancer, especially for GC patients with aberrant MAPK signalling or mTOR signalling.

[Anti-tumor effect of Huaier extract supernatant on human gastric cancer HGC-27 and MGC-803 cells].

The purpose of this study was to investigate the effect of Huaier extract supernatant(HES) on the proliferation, apoptosis, autophagy, and migration of human gastric cancer HGC-27 and MGC-803 cells and its molecular mechanisms. The main components in HES were preliminarily analyzed by high-performance liquid chromatography-mass spectrometry(HPLC-MS). Methyl thiazolyl tetrazolium(MTT) assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine(EdU) staining assay were used to explore the effect of HES on the proliferation of human gastric cancer HGC-27 and MGC-803 cells. Hoechst staining and flow cytometry assay were used to determine the effect of HES on apoptosis of human gastric cancer HGC-27 and MGC-803 cells. Acridine orange staining and cell scratch assay were used to determine the effect of HES on autophagy and migration of human gastric cancer HGC-27 and MGC-803 cells, respectively. Western blot was used to investigate the regulatory effect of HES on the expression levels of proteins related to apoptosis, epithelial-mesenchymal transition(EMT), and signaling pathways in human gastric cancer HGC-27 and MGC-803 cells. The results showed that HES mainly contained some components with high polarities. HES significantly reduced the cell viability of human gastric cancer cells in a dose-and time-dependent manner. The IC_(50 )values after 48 h of HES treatment in human gastric cancer HGC-27 and MGC-803 cells were 7.56 and 10.77 g·L~(-1), respectively. Meanwhile, HES inhibited the colony-forming ability and short-term proliferation of human gastric cancer cells. The apoptosis rates of HGC-27 and MGC-803 cells treated with 8 g·L~(-1) HES for 72 h were 62.13%±8.92% and 54.50%±3.26%, respectively. HES also promoted autophagy in human gastric cancer cells and impaired their migration ability in vitro. Moreover, HES up-regulated the cleavage of the apoptosis marker poly ADP-ribose polymerase(PARP) and the protein expression level of the epithelial cell marker E-cadherin, and down-regulated the protein levels of phosphorylated-mammalian target of rapamycin(p-mTOR), phosphorylated-S6(p-S6), and phosphorylated-extracellular signal-regulated kinase(p-ERK) in human gastric cancer cells. Therefore, HES is one of the effective anti-tumor components of Huaier, which inhibits the proliferation and migration of human gastric cancer cells, and induces apoptosis and autophagy. Moreover, the mTOR signal and ERK signal may be involved in the anti-gastric cancer effect of HES. This study provides novel references for the in-depth research and clinical application of Huaier. It is also of great significance to promote the scientific development and utilization of Huaier.

[Research progress on anti-tumor effect of Chinese dragon's blood].

As a traditional Chinese medicine, Chinese dragon's blood has multiple effects, such as activating blood to remove blood stasis, softening and dispelling stagnation, astringent and hemostasis, clearing swelling and relieving pain, regulating menstruation and rectifying the blood, so it is called "an effective medicine of promoting blood circulation". It has been widely used clinically to treat a variety of diseases. With the further research on Chinese dragon's blood, its anti-tumor medicinal value is gradually emerging. Modern pharmacological studies have shown that Chinese dragon's blood exerts anti-tumor effects mainly by inhibiting cell proliferation, inducing apoptosis, inducing DNA damage and cell cycle arrest, inducing senescence and autophagy of tumor cells, inhibiting metastasis and angiogenesis, as well as reversing multidrug resistance. This article focuses on the research progress on anti-tumor effects of Chinese dragon's blood extract and its chemical components, with a view to provide new references for the in-depth research and reasonable utilization of Chinese dragon's blood.